Commentary
Cancer immunotherapy has gained significant interest and widespread clinical application over the past few decades [1]. The development of immune checkpoint inhibitor (ICI) antibodies that block inhibitory pathways (e.g., CTLA-4, PD-1/PD-L1) has introduced a groundbreaking new approach to cancer treatment, shifting the focus from targeting tumor cells to modulating the patient's immune response [2,3]. Reversing T-cell exhaustion enables T cells, NK cells, and dendritic cells to overcome immunosuppression and effectively attack tumor cells, thereby improving therapeutic outcomes across various cancers. Their promising therapeutic efficacy has further advanced this field [4].
Aside from checkpoint inhibitors, immunotherapeutic strategies include a wide range of approaches, such as naked antibodies (e.g., trastuzumab [5], cetuximab [6], rituximab [7], bevacizumab [8]) and their modifications, including bispecific antibodies (e.g., blinatumomab [9], teclistamab [10]), trispecific antibodies [11], antibody-drug conjugates (ADCs) (e.g., brentuximab vedotin [12], trastuzumab emtansine [13], sacituzumab govitecan-hziy [14]), engineered immune cells (CAR-T and CAR-NK cells) [15], vaccines (mRNA) [16], cytokines [17], oncolytic viruses, and more recently, small molecules, peptides, nanoparticles, gene therapy, and exosomes aimed at targeting the tumor microenvironment (TME) [18]. These advances have transformed oncology practice, establishing immunotherapy as a central pillar of modern cancer treatment alongside surgery, chemotherapy, and radiotherapy [18,19].
Although these therapies have improved outcomes for some patients and offer long-term clinical benefits, their widespread use in cancer immunotherapy remains limited by challenges, including highly variable response rates, immunotherapy resistance, and immune-related adverse events (irAEs). Several obstacles need to be addressed. Therapy response rates vary by type, ranging from 20% to 40% with ICI [4], 50-90% with CAR-T cells [20], and 73% with CAR-NK cells [21]. In addition, some patients (10%-30%) can experience hyper-progressive disease [22]. Some patients experience lasting clinical benefits, and in some cases, even a cure. However, most tumors do not respond. Common challenges include primary resistance (never responding to immunotherapy), secondary resistance (initial response followed by treatment failure), and progression after stopping therapy [23]. Biological regulatory mechanisms underlying resistance include tumor cell-intrinsic factors, such as defects in the antigen presentation machinery, genetic alterations in the IFN-g signaling pathway, oncogenic signaling, and epigenetic reprogramming; as well as extrinsic factors related to the TME [4]. An important challenge is irAEs, where immunotherapy-related toxicity can harm normal host tissue [24]. These events can range from mild to severe and [25], even be fatal, involving almost every organ [26–28]. Toxicities associated with CAR-T cell therapy include cytokine release syndrome (CRS) and neurologic toxicity, such as immune effector cell-associated neurotoxicity syndrome (ICANS) [29,30].
Therefore, it is essential to identify biomarkers that predict response and resistance, as well as the risk of irAEs and toxicity. These biomarkers will be key for selecting patients likely to benefit from immunotherapy, identifying those at high risk of toxicity, and ultimately developing alternative treatment strategies.
Today, standard clinical practice uses biomarkers to select patients for immunotherapy based on specific clinical scenarios. An active anti-tumor immune response is a crucial prerequisite for predicting response to ICI therapy. The most common way to assess this response is by evaluating the presence of T cells in tumor tissue biopsies. High levels of pre-existing CD8+ T cells expressing PD-1, located at the invasive tumor margin of metastatic melanoma tissue before anti-PD-1 therapy, are associated with tumor regression [31]. Another approach involves identifying gene expression profiling (GEP) associated with immune cell activation via RNA sequencing and may represent a complementary approach to PD-L1 evaluation. Transcriptome analysis of biopsies from advanced melanoma treated with nivolumab (anti-PD-1) alone or in combination with ipilimumab (anti-CTLA-4) revealed that T cell infiltration and IFN-g signaling signatures strongly correlate with clinical response to therapy [32].
The assessment of PD-L1 expression in the TME using immunohistochemistry (IHC) is currently the most widely used clinical biomarker for evaluating pretreatment tumor tissue and predicting response to anti-PD-1/PD-L1 therapies [33], as PD-L1 expression was the first biomarker associated with anti-PD-1 therapy response [34]. However, PD-L1 evaluation by IHC has several limitations, including dynamic and heterogeneous expression, uncertain positivity threshold and scoring reproducibility, and differences in predictive significance between tumor and immune cell expression.
The advent of next-generation sequencing (NGS) revealed wide variation in the number of somatic mutations within a given tumor type and across tumors [35,36]. The tumor mutational burden (TMB) is associated with greater benefit from ICI therapy, with high TMB associated with higher response rates. However, NGS may be somewhat challenging to perform in the clinic [37].
Recently, quantifying multiple protein markers using multiplex immunohistochemistry/immunofluorescence (mIHC/IF) has become a promising method for identifying predictive tissue-based biomarkers of response to immunotherapies [38]. mIHC/IF enables the simultaneous visualization of multiple protein markers in situ on the same tissue section and allows for single-cell-resolution assessment of the spatial relationships between different cell types, including their locations within TME compartments [39]. Furthermore, mIHC/IF has been shown to be associated with improved performance over PD-L1 IHC, TMB, or GEP alone in predicting response to anti–PD-1/PD-L1 treatment [33].
Regarding engineered T and NK cells, extensive research has been conducted to develop biomarkers that predict immune responses to CAR-T and CAR-NK cell infusions, including susceptibility to toxicity, therapeutic effectiveness, and long-term remission [40,41]. Recently, a combination of multiparameter flow cytometry and circulating cytokine levels has been used to identify predictive biomarkers of response to CAR-T cell therapy in pan-hematologic cancers [42,43]. A significantly reduced risk of toxicity is associated with CAR-NK cells compared with CAR-T cells [44,45].
An ideal biomarker should possess specificity, predictive accuracy, reproducibility, clinical accessibility, and mechanistic informativeness. Tumor biomarkers can face context-dependent limitations, including tissue availability and quality, timing of sample collection (e.g., longitudinal biospecimens), resolution, specificity, sensitivity, and effectiveness across different cancer types (universal use/application), as well as the complexity and cost of the technology. Currently, there are no established predictive biomarkers for evaluating very early on-treatment response or resistance (pharmacodynamic). Non-invasive methods like imaging technologies and liquid biopsies would be highly valuable for routine use by patients and healthcare providers.
Over the past decade, research on circulating non-coding RNAs (ncRNAs) as blood biomarkers has grown rapidly. Because of their high abundance and stability, circulating ncRNAs hold promise as a non-invasive liquid biopsy for providing insights into tumor biology and the effects of treatments such as targeted therapies and immunotherapies [46]. In our previous publication, we found that elevated serum levels of miR-19a-3p were associated with a favorable prognosis in patients with metastatic HER2 + breast cancer treated with trastuzumab [47]. We sought to understand the underlying mechanism and the origin of miR-19a-3p. In our recent publication [48], we discovered that the high levels of miR-19a-3p in the blood of patients with metastatic HER2 + breast cancer may result from a combination of effective NK cell-mediated Antibody-Dependent Cellular Cytotoxicity (ADCC) and activation of CD4+ Th1 cells, both associated with a favorable prognosis [49,50]. Specifically, trastuzumab-induced NK cell-mediated ADCC in vitro triggered the release of miR-19a-3p from HER2+ tumor cells, which naturally express high levels of miR-19a-3p, during apoptosis and cell death. When trastuzumab engages CD16, it prompts NK cells to secrete IFN-g [51], and T cell–recruiting chemokines (IL-8, RANTES, MIP-1α, MIP-1β, MCP-1, MDC) [52], crucial for CD4+ Th1 cell differentiation and promoting anti-tumor immune responses [53]. We also observed that polarized CD4+ Th1 cells expressed and secreted higher levels of miR-19a-3p than CD4+ Th2 cells, and that restimulation with anti-CD3/CD28 further increased both. Interestingly, CD4+ Th1 cells that acquired a central memory T (TCM) phenotype (CD45RO+ CCR7+ CD62L+), during long-term in vitro cell culture, also expressed and secreted high levels of miR-19a-3p. Since miR-19a-3p regulates PTEN and BCL2L11, genes integral to sustaining proliferation, cytokine secretion in T helper cells, and resistance to apoptosis in T cells [54–56], higher miR-19a-3p expression levels can enhance the expansion, survival, and functions of CD4+ Th1 cells. Finally, we found that patients with metastatic HER2 + breast cancer, good prognosis, and high serum miR-19a-3p levels had a higher proportion of CD4+ IL-2+ T cells relative to CD4+ IL-4+ T cells, an increased percentage of CD56Bright NK cells, and a trend toward a higher ratio of CD4+ IFN-g+/CD4+ IL-4+ T cells in their peripheral blood compared to those with poor prognosis and low serum miR-19a-3p levels.
We concluded that high levels of miR-19a-3p, associated with a favorable prognosis in patients with metastatic HER2 + breast cancer treated with trastuzumab, may be due to the effective activation of key anti-tumor immune response mechanisms. Specifically, an effective ADCC activates NK cells, which not only kill tumor cells but also promote anti-tumor immune responses by secreting IFN-g and immune cell-recruiting chemokines to the TME (IL-8, MIP-1α, MIP-1β, MCP-1, and RANTES). IFN-g promotes the activation, maturation, and antigen presentation by DCs [57], and the differentiation of naïve CD4+ T cells into CD4+ Th1 effector cells [58]. IFN-g from CD4+ Th1 cells further activate DCs to secrete IL-12 and enhances cross-presentation of tumor-associated antigens [57,59]. In turn, IL-12, combined with IFN-g, promotes CD4+ Th1 cell polarization, increases the cytotoxic activity and IFN-g production in NK cells, and induces the generation and activation of cytotoxic CD8+ T lymphocytes (CTLs) [51,60–63]. Finally, IL-2 from CD4+ Th1 cells, together with IFN-g, enhances the proliferation and cytotoxic activity of CD8+ CTLs and NK cells, thereby supporting tumor cell killing [64,65]. In summary, high miR-19a-3p levels may reflect an active anti-tumor immune response in the TME (“hot” TME).
On the other hand, ineffective NK cell-mediated ADCC not only results in reduced tumor cell killing but also decreases the production of IFN-g and chemokines by NK cells, leading to a diminished ability to trigger an effective CD4+ Th1-mediated anti-tumor immune response. This could explain the poor prognosis of patients with low serum miR-19a-3p levels. Notably, an immunosuppressive TME, characterized by IL-10, TGF-β, PD-L1, MDSCs, and CD4+ Treg cells, can render NK cells dysfunctional, thereby hindering effective NK cell-mediated ADCC [66], and cytokine and chemokine secretion. Low levels of miR-19a-3p may reflect an immunosuppressed TME, or "cold” TME (Figure 1).
Our findings could potentially be applied to studying the activation of ADCC and CD4+ Th1-mediated immune responses triggered by other ADCC-inducing antibodies across various cancer types, such as anti-EGFR cetuximab in metastatic colon cancer, head and neck cancer (HNSCC), triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), the anti-CD20 rituximab in chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL). The potential applications of our findings may also extend to evaluating the effectiveness of blood levels of miR-19a-3p in assessing CAR-T cell activation and identifying patients who may respond to CAR cell therapy. CAR CD4+ T cells with Th1 polarization provide essential help with therapeutic responses, improving persistence and cytokine production like IFN-g [67,68]. Furthermore, in CAR-T and CAR-NK cells, CAR engagement with specific targets can induce higher levels of IFN-g than in native T and NK cells [69].
As we mentioned earlier, an active anti-tumor immune response is crucial for predicting response to ICI therapy. Therefore, a biomarker that can assess a pre-existing immune cell-mediated anti-tumor response would be valuable for identifying patients who are likely to benefit from ICI therapy. In this context, recognizing an active and effective CD4+ Th1 cell-mediated response is essential for treatment decisions. In fact, CD4+ Th1-mediated functions are important for effective anti-tumor responses, as they support the proliferation and cytotoxic activity of CD8+ CTLs and NK cells. The levels of CD4+ Th1 cells infiltrating the TME are associated with favorable clinical outcomes [70], and pre-existing CD4+ Th1 responses are associated with better clinical outcomes in patients treated with ICIs [71–74]. Our funding could be used to evaluate the presence of an active CD4+ Th1 cell-mediated response and to monitor its levels over time in longitudinal biospecimens (at baseline and on-treatment) in cancer patients treated with ICI.
We propose miR-19a-3p as a potential blood biomarker for effective NK cell-mediated ADCC and CD4+ Th1 cell effector functions in patients with metastatic HER2+ breast cancer treated with trastuzumab, and prediction of their clinical outcomes. Specifically, blood levels of miR-19a-3p could help identify patients with activated anti-tumor immune responses who might benefit from this therapy. We believe that the advantage of blood miR-19a-3p as a minimally invasive biomarker is its ability to serve as a valuable pharmacodynamic indicator, providing early evidence of ongoing anti-tumor immune activity or resistance, thereby aiding treatment decision-making. Additionally, as a blood biomarker, it allows for continuous, “real-time” sampling to monitor the activation status of tumor immunity (longitudinal biospecimens), such as ADCC and Th1-mediated responses. The use of miR-19a-3p as a blood tumor biomarker could potentially be a complementary tool alongside other clinical tools, such as diagnostic imaging and pathology assessments. Since our retrospective studies were conducted in a relatively small patient cohort, these findings need to be confirmed in a prospective study with a larger patient cohort.
Funding
This work was supported by NIH grants R01DE032018-01/PID14232.
References
2. Zhou P. Role of tumor microenvironment in regulator of tumor progression and immunotherapy. Discov Oncol. 2026 Jan 19;17(1):331.
3. Petitprez F, Meylan M, de Reyniès A, Sautès-Fridman C, Fridman WH. The Tumor Microenvironment in the Response to Immune Checkpoint Blockade Therapies. Front Immunol. 2020 May 7; 11:784.
4. Sharma P, Goswami S, Raychaudhuri D, Siddiqui BA, Singh P, Nagarajan A, et al. Immune checkpoint therapy-current perspectives and future directions. Cell. 2023 Apr 13;186(8):1652–69.
5. Hudis CA. Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med. 2007 Jul 5;357(1):39–51.
6. Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007 Nov 15;357(20):2040–8.
7. Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, et al. Rituximab in B-Lineage Adult Acute Lymphoblastic Leukemia. N Engl J Med. 2016 Sep 15;375(11):1044–53.
8. Keating GM. Bevacizumab: a review of its use in advanced cancer. Drugs. 2014 Oct;74(16):1891–925.
9. Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017 Mar 2;376(9):836–47.
10. Moreau P, Garfall AL, van de Donk NWCJ, Nahi H, San-Miguel JF, Oriol A, et al. Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2022 Aug 11;387(6):495–505.
11. Koh KN, Kim DH, Kim H. Trispecific T cell engagers in hematological malignancies: Advancing beyond bispecific antibodies. Semin Hematol. 2025 Aug;62(4):350–6.
12. Berger GK, McBride A, Lawson S, Royball K, Yun S, Gee K, Bin Riaz I, Saleh AA, Puvvada S, Anwer F. Brentuximab vedotin for treatment of non-Hodgkin lymphomas: A systematic review. Crit Rev Oncol Hematol. 2017 Jan; 109:42–50.
13. Peddi PF, Hurvitz SA. Trastuzumab emtansine: the first targeted chemotherapy for treatment of breast cancer. Future Oncol. 2013 Mar;9(3):319–26.
14. Cortés J, Punie K, Barrios C, Hurvitz SA, Schneeweiss A, Sohn J, et al. Sacituzumab Govitecan in Untreated, Advanced Triple-Negative Breast Cancer. N Engl J Med. 2025 Nov 13;393(19):1912–25.
15. Peng L, Sferruzza G, Yang L, Zhou L, Chen S. CAR-T and CAR-NK as cellular cancer immunotherapy for solid tumors. Cell Mol Immunol. 2024 Oct;21(10):1089–108.
16. Yaremenko AV, Khan MM, Zhen X, Tang Y, Tao W. Clinical advances of mRNA vaccines for cancer immunotherapy. Med. 2025 Jan 10;6(1):100562.
17. Berraondo P, Sanmamed MF, Ochoa MC, Etxeberria I, Aznar MA, Pérez-Gracia JL, et al. Cytokines in clinical cancer immunotherapy. Br J Cancer. 2019 Jan;120(1):6–15.
18. Zhang M, Liu C, Tu J, Tang M, Ashrafizadeh M, Nabavi N, et al. Advances in cancer immunotherapy: historical perspectives, current developments, and future directions. Mol Cancer. 2025 May 7;24(1):136.
19. Bandara S, Raveendran S. Current Landscape and Future Directions in Cancer Immunotherapy: Therapies, Trials, and Challenges. Cancers (Basel). 2025 Feb 27;17(5):821.
20. June CH, Sadelain M. Chimeric Antigen Receptor Therapy. N Engl J Med. 2018 Jul 5;379(1):64–73.
21. Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, et al. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N Engl J Med. 2020 Feb 6;382(6):545–53.
22. Champiat S, Ferrara R, Massard C, Besse B, Marabelle A, Soria JC, et al. Hyperprogressive disease: recognizing a novel pattern to improve patient management. Nat Rev Clin Oncol. 2018 Dec;15(12):748–62.
23. Emens LA, Romero PJ, Anderson AC, Bruno TC, Capitini CM, Collyar D, et al. Challenges and opportunities in cancer immunotherapy: a Society for Immunotherapy of Cancer (SITC) strategic vision. J Immunother Cancer. 2024 Jun 19;12(6):e009063.
24. Mangani D, Yang D, Anderson AC. Learning from the nexus of autoimmunity and cancer. Immunity. 2023 Feb 14;56(2):256–71.
25. Dougan M, Luoma AM, Dougan SK, Wucherpfennig KW. Understanding and treating the inflammatory adverse events of cancer immunotherapy. Cell. 2021 Mar 18;184(6):1575–88.
26. Goswami S, Siddiqui BA, Subudhi SK, Basu S, Yadav SS, Diab A, et al. A composite T cell biomarker in pre-treatment blood samples correlates with detection of immune-related adverse events. Cancer Cell. 2022 Mar 14;40(3):249–51.
27. Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med. 2018 Jan 11;378(2):158–68.
28. Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins S, Anadkat M, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. J Clin Oncol. 2021 Dec 20;39(36):4073–126.
29. Brudno JN, Kochenderfer JN. Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management. Blood Rev. 2019 Mar; 34:45–55.
30. Santomasso BD, Nastoupil LJ, Adkins S, Lacchetti C, Schneider BJ, Anadkat M, et al. Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. J Clin Oncol. 2021 Dec 10;39(35):3978–92.
31. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014 Nov 27;515(7528):568–71.
32. Grasso CS, Tsoi J, Onyshchenko M, Abril-Rodriguez G, Ross-Macdonald P, Wind-Rotolo M, et al. Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma. Cancer Cell. 2020 Oct 12;38(4):500–15e3.
33. Lu S, Stein JE, Rimm DL, Wang DW, Bell JM, Johnson DB, et al. Comparison of Biomarker Modalities for Predicting Response to PD-1/PD-L1 Checkpoint Blockade: A Systematic Review and Meta-analysis. JAMA Oncol. 2019 Aug 1;5(8):1195–204.
34. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366(26):2443–54.
35. Caldas C, Davies HR, Desmedt C, Eils R, Eyfjörd JE, Foekens JA, et al. Signatures of mutational processes in human cancer. Nature. 2013 Aug 22;500(7463):415–21.
36. Gubin MM, Schreiber RD. CANCER. The odds of immunotherapy success. Science. 2015 Oct 9;350(6257):158–9.
37. Goodman RS, Jung S, Balko JM, Johnson DB. Biomarkers of immune checkpoint inhibitor response and toxicity: Challenges and opportunities. Immunol Rev. 2023 Sep;318(1):157–66.
38. Sheng W, Zhang C, Mohiuddin TM, Al-Rawe M, Zeppernick F, Falcone FH, et al. Multiplex Immunofluorescence: A Powerful Tool in Cancer Immunotherapy. Int J Mol Sci. 2023 Feb 4;24(4):3086.
39. Taube JM, Sunshine JC, Angelo M, Akturk G, Eminizer M, Engle LL, et al. Society for Immunotherapy of Cancer: updates and best practices for multiplex immunohistochemistry (IHC) and immunofluorescence (IF) image analysis and data sharing. J Immunother Cancer. 2025 Jan 8;13(1):e008875.
40. Levstek L, Janžič L, Ihan A, Kopitar AN. Biomarkers for prediction of CAR T therapy outcomes: current and future perspectives. Front Immunol. 2024 Mar 15;15:1378944.
41. Shao R, Li Z, Xin H, Jiang S, Zhu Y, Liu J, et al. Biomarkers as targets for CAR-T/NK cell therapy in AML. Biomark Res. 2023 Jun 17;11(1):65.
42. Chen GM, Jain A, Gering DT, Satulovsky J, Datta S, Lai P, et al. Predictive biomarkers of response to chimeric antigen receptor (CAR) T-cell therapy for pan-haematologic cancer. Nat Biomed Eng. 2026 Apr;10(4):803–14.
43. Yoo KH, Szymura S, Dong Z, Kandel A, Cha SC, Kwak LW. Predictive markers for the efficacy of CAR T-cell therapy: the interplay between CAR T-cell fitness and systemic immunity. Blood Adv. 2025 Dec 23;9(24):6432–42.
44. Marin D, Li Y, Basar R, Rafei H, Daher M, Dou J, et al. Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial. Nat Med. 2024 Mar;30(3):772–84.
45. Sabha Y, Kim SH, Tseng HC, Byrne ME, Tsao WC, Lee SH, et al. CD147-CAR-NK cell therapy shows minimal toxicities in human CD147 transgenic mouse model with solid tumors. Mol Ther Oncol. 2025 Feb 26;33(1):200957.
46. Alahdal M, Elkord E. Non-coding RNAs in cancer immunotherapy: Predictive biomarkers and targets. Clin Transl Med. 2023 Sep;13(9):e1425.
47. Anfossi S, Giordano A, Gao H, Cohen EN, Tin S, Wu Q, et al. High serum miR-19a levels are associated with inflammatory breast cancer and are predictive of favorable clinical outcome in patients with metastatic HER2+ inflammatory breast cancer. PLoS One. 2014 Jan 8;9(1):e83113.
48. Cohen EN, Gao H, Tin S, Wu Q, Ivan C, Ueno NT, et al. High levels of circulating miR-19a-3p in patients with metastatic HER2 + breast cancer are associated with a favorable prognosis and anti-tumor immune responses. Breast Cancer Res. 2026 Jan 26;28(1):3.
49. Beano A, Signorino E, Evangelista A, Brusa D, Mistrangelo M, Polimeni MA, et al. Correlation between NK function and response to trastuzumab in metastatic breast cancer patients. J Transl Med. 2008 May 16; 6:25.
50. Datta J, Fracol M, McMillan MT, Berk E, Xu S, Goodman N, et al. Association of Depressed Anti-HER2 T-Helper Type 1 Response With Recurrence in Patients With Completely Treated HER2-Positive Breast Cancer: Role for Immune Monitoring. JAMA Oncol. 2016 Feb;2(2):242–6.
51. Roda JM, Joshi T, Butchar JP, McAlees JW, Lehman A, Tridandapani S, et al. The activation of natural killer cell effector functions by cetuximab-coated, epidermal growth factor receptor positive tumor cells is enhanced by cytokines. Clin Cancer Res. 2007 Nov 1;13(21):6419–28.
52. Roda JM, Parihar R, Magro C, Nuovo GJ, Tridandapani S, Carson WE 3rd. Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. Cancer Res. 2006 Jan 1;66(1):517–26.
53. Agnello D, Lankford CS, Bream J, Morinobu A, Gadina M, O'Shea JJ, et al. Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights. J Clin Immunol. 2003 May;23(3):147–61.
54. Suzuki A, Yamaguchi MT, Ohteki T, Sasaki T, Kaisho T, Kimura Y, et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity. 2001 May;14(5):523–34.
55. Soond DR, Garçon F, Patton DT, Rolf J, Turner M, Scudamore C, et al. Pten loss in CD4 T cells enhances their helper function but does not lead to autoimmunity or lymphoma. J Immunol. 2012 Jun 15;188(12):5935–43.
56. Bouillet P, O'Reilly LA. CD95, BIM and T cell homeostasis. Nat Rev Immunol. 2009 Jul;9(7):514–9.
57. Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to interferon-gamma. Annu Rev Immunol. 1997; 15:749–95.
58. Martín-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, Lanzavecchia A, et al. Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat Immunol. 2004 Dec;5(12):1260–5.
59. Lee SC, Srivastava RM, López-Albaitero A, Ferrone S, Ferris RL. Natural killer (NK): dendritic cell (DC) cross talk induced by therapeutic monoclonal antibody triggers tumor antigen-specific T cell immunity. Immunol Res. 2011 Aug;50(2-3):248–54.
60. Heufler C, Koch F, Stanzl U, Topar G, Wysocka M, Trinchieri G, et al. Interleukin-12 is produced by dendritic cells and mediates T helper 1 development as well as interferon-gamma production by T helper 1 cells. Eur J Immunol. 1996 Mar;26(3):659–68.
61. Parihar R, Dierksheide J, Hu Y, Carson WE. IL-12 enhances the natural killer cell cytokine response to Ab-coated tumor cells. J Clin Invest. 2002 Oct;110(7):983–92.
62. Jaime-Ramirez AC, Mundy-Bosse BL, Kondadasula S, Jones NB, Roda JM, Mani A, et al. IL-12 enhances the antitumor actions of trastuzumab via NK cell IFN-γ production. J Immunol. 2011 Mar 15;186(6):3401–9.
63. Mehrotra PT, Wu D, Crim JA, Mostowski HS, Siegel JP. Effects of IL-12 on the generation of cytotoxic activity in human CD8+ T lymphocytes. J Immunol. 1993 Sep 1;151(5):2444–52.
64. Konjević GM, Vuletić AM, Mirjačić Martinović KM, Larsen AK, Jurišić VB. The role of cytokines in the regulation of NK cells in the tumor environment. Cytokine. 2019 May; 117:30–40.
65. Schomburg A, Menzel T, Korfer A, Heer G, Dallmann I, Kirchner H, et al. In vivo and ex vivo antitumor activity in patients receiving low-dose subcutaneous recombinant interleukin-2. Nat Immun. 1992;11(3):133–43.
66. Cózar B, Greppi M, Carpentier S, Narni-Mancinelli E, Chiossone L, Vivier E. Tumor-Infiltrating Natural Killer Cells. Cancer Discov. 2021 Jan;11(1):34–44.
67. Xhangolli I, Dura B, Lee G, Kim D, Xiao Y, Fan R. Single-cell Analysis of CAR-T Cell Activation Reveals A Mixed TH1/TH2 Response Independent of Differentiation. Genomics Proteomics Bioinformatics. 2019 Apr;17(2):129–39.
68. Galli E, Bellesi S, Pansini I, Di Cesare G, Iacovelli C, Malafronte R, et al. The CD4/CD8 ratio of infused CD19-CAR-T is a prognostic factor for efficacy and toxicity. Br J Haematol. 2023 Nov;203(4):564–70.
69. Egli L, Kaulfuss M, Mietz J, Picozzi A, Verhoeyen E, Münz C, et al. CAR T cells outperform CAR NK cells in CAR-mediated effector functions in head-to-head comparison. Exp Hematol Oncol. 2024 May 14;13(1):51.
70. Bruni D, Angell HK, Galon J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat Rev Cancer. 2020 Nov;20(11):662–80.
71. Kagamu H, Kitano S, Yamaguchi O, Yoshimura K, Horimoto K, Kitazawa M, et al. CD4+ T-cell Immunity in the Peripheral Blood Correlates with Response to Anti-PD-1 Therapy. Cancer Immunol Res. 2020 Mar;8(3):334–44.
72. Spitzer MH, Carmi Y, Reticker-Flynn NE, Kwek SS, Madhireddy D, Martins MM, et al. Systemic Immunity Is Required for Effective Cancer Immunotherapy. Cell. 2017 Jan 26;168(3):487–502.
73. Zuazo M, Arasanz H, Bocanegra A, Fernandez G, Chocarro L, Vera R, et al. Systemic CD4 Immunity as a Key Contributor to PD-L1/PD-1 Blockade Immunotherapy Efficacy. Front Immunol. 2020 Nov 30;11:586907.
74. Thibaudin M, Fumet JD, Chibaudel B, Bennouna J, Borg C, Martin-Babau J, et al. First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b/2 trial. Nat Med. 2023 Aug;29(8):2087–98.