Modeling the Specific CD4+ T Cell Response against a Tumor Neoantigen

Abstract

The antitumor activity of CD4+ T cells is increasingly acknowledged in both humans and mice. The involved mechanisms have been mostly studied using transplanted tumor mouse systems. In these models, many tumor cells die at the time of implantation leading to the release of Ag in an inflammatory context contrasting with the slow and nondestructive growth of early-stage human tumors. In this study, we show that the presentation of a MHC class II–restricted model Ag (male, DBY) released by dying tumor cells may last more than 4 wk. The duration of Ag presentation varies according to the way the cells are killed before implantation. To avoid this artifactual early priming of the host precluding the study of the interactions between the immune system and tumors at the steady state, we generated a cell line expressing the DBY Ag in an inducible manner. Ag expression can be efficiently induced in vivo several days after tumor implantation. We show that the Ag reaches the lymph node and activates naive CD4+ T cells to proliferate and recirculate. We did not observe de novo induction of tumor-specific regulatory T cells. However, we observed Th1/Th17 effector cells in the tumor draining lymph node and tumors. Thus, when a neoantigen appears in established tumors, the immune system is not ignorant and naive CD4+ T cells are not tolerized. This opens up the possibility of therapeutic vaccines improving the immune response toward tumor-specific neoantigens.

Tumour‐specific CD4 T cells eradicate melanoma via indirect recognition of tumour‐derived antigen

“…Thus, the bulk of tumour antigen in our model reached draining nodes in a DC-associated form, rather than as free antigen, suggesting that any 'accidental' release of tumour antigen was unlikely to have a major role in the induction of anti-tumour immunity. 33 A requirement for host APCs to prime naive tumour-reactive CD4 T cells has been reported even in those models in which direct MHCII-dependent interaction between tumour and CD4 T cells was demonstrated, 3 indicating that CD4 T-cell priming in cancer follows the same rules as priming to foreign antigen.…”

Comprehensive genomic and immunophenotypic analysis of CD4 T cell infiltrating human triple-negative breast cancer

“…Most neoantigens of cancer cells can stimulate T cells and also induce a regulatory immune response [ 7 , 8 ]. Intratumoral CD4 + T cells are increasingly recognized as responsible for antitumor immune response and the production of inflammatory mediators that induce tumor growth, invasion, angiogenesis, and metastasis which are associated with clinical outcomes [ 9 , 10 ].…”

CIMT 2017: Anniversary symposium - Report on the 15th CIMT Annual Meeting of the Association for Cancer Immunotherapy

“…By generating an MCA101-based tumor cell line with inducible expression of the MHC-II restricted model antigen DBY, Flament and colleagues demonstrated that antigen release from tumor cells results in efficient priming of tumor-specific, polyfunctional CD4 + T cells in the tumor draining lymph node capable of circulating to the tumor and secrete IFN-γ. 58 Notably, this tumor model will be very useful to gain a better understanding of how to efficiently generate antitumor CD4 + T cell responses for therapeutic purposes.…”