Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts

By Sergio A. Quezada, T. Simpson, K. Peggs, T. Merghoub, J. Vider, Xiaozhou Fan, R. Blasberg, H. Yagita, P. Muranski, P. Antony and 2 more. Journal of Experimental Medicine, 2010

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Adoptive transfer of large numbers of tumor-reactive CD8+ cytotoxic T lymphocytes (CTLs) expanded and differentiated in vitro has shown promising clinical activity against cancer. However, such protocols are complicated by extensive ex vivo manipulations of tumor-reactive cells and have largely focused on CD8+ CTLs, with much less emphasis on the role and contribution of CD4+ T cells. Using a mouse model of advanced melanoma, we found that transfer of small numbers of naive tumor-reactive CD4+ T cells into lymphopenic recipients induces substantial T cell expansion, differentiation, and regression of large established tumors without the need for in vitro manipulation. Surprisingly, CD4+ T cells developed cytotoxic activity, and tumor rejection was dependent on class II–restricted recognition of tumors by tumor-reactive CD4+ T cells. Furthermore, blockade of the coinhibitory receptor CTL-associated antigen 4 (CTLA-4) on the transferred CD4+ T cells resulted in greater expansion of effector T cells, diminished accumulation of tumor-reactive regulatory T cells, and superior antitumor activity capable of inducing regression of spontaneous mouse melanoma. These findings suggest a novel potential therapeutic role for cytotoxic CD4+ T cells and CTLA-4 blockade in cancer immunotherapy, and demonstrate the potential advantages of differentiating tumor-reactive CD4+ cells in vivo over current protocols favoring in vitro expansion and differentiation.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/e3aa1ac184ac133319a3cc8193482f3641c77828

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Citations in the corpus

Adoptive immunotherapy for cancer: harnessing the T cell response (2012, neutral): “Üstelik CD4+ T hücrelerin, CD8+ T hücrelerinin görevlerini arttırmanın yanında tümör eliminasyonunda da daha doğrudan bir rolü vardır (137,138).”
The polarization of immune cells in the tumour environment by TGFβ (2010, background): “Recent findings indicate that the differentiation state of T cells, in terms of naive versus effector or memory cells, might also be important for mounting more efficient antitumour responses as single transfers of naive CD4 + T cells were able to eradicate established tumours independently of CD8 ”
Revisiting the role of CD4+ T cells in cancer immunotherapy—new insights into old paradigms (2020, result): “previous work from a decade ago [45, 46] and found that tumour-infiltrating TH1-like CD4 + T cells acquired cytotoxicity against B16 melanoma.”
Therapeutic cancer vaccines. (2010, background): “Quite apart from these CD8+ T cell–supporting roles, CD4+ T cells have intrinsic effector functions (121, 127).”
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma (2013, result): “In agreement with prior work (Quezada et al., 2006, 2010; Liakou et al., 2008; Waitz et al., 2012), –CTLA-4 significantly enhanced the intratumoral CD4+Foxp3/CD4+Foxp3+ (T eff/T reg cell) ratio (Fig.”