A role for T helper cells in anti–CTLA-4 therapy

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Science Immunology  01 Sep 2017:
Vol. 2, Issue 15, eaao6871
DOI: 10.1126/sciimmunol.aao6871


Comparison of immune responses to CTLA4 and PD-1 blockade uncovers a role for helper T cells in anti–CTLA-4 therapy.

Immune checkpoint blockade (ICB) with either anti–CTLA-4 or anti–PD-1 monoclonal antibodies enhances antitumor T cell immunity, but it has been unclear whether they act via similar or distinct mechanisms. Only a minority of patients respond to ICB, and knowledge of possibly different but synergistic mechanisms should facilitate development of more widely effective therapies.

Wei et al. used mass cytometry to characterize tumor infiltrating lymphocytes (TILs) extracted from partially regressing tumors of mice and humans treated with either anti–CTLA-4 or anti–PD-1 monoclonal antibodies. They compared untreated or ICB treated mice with either MC38 carcinomas or B16BL6 melanomas. Among many different T cell populations within the tumors, only a few subsets were expanded with ICB therapy. Both anti–CTLA-4 and anti–PD-1 therapies induced expansion of CD8+ T cells with a PD-1hi exhausted phenotype. However, only anti–CTLA-4 therapy induced a significant expansion of ICOS+ TBET+ TH1-like CD4+ T cells. Remarkably, the phenotypes of the expanded T cell populations in both tumor types were the same, even though the MC38 and B16BL6 models differ in many ways.

The investigators also did mass cytometry of TILs in melanomas removed from patients treated with anti–CTLA-4 or anti–PD-1. Of 19 distinguishable T cell subsets, only 2 were significantly expanded in the tumors of ICB-treated patients compared with normal blood. These included a CD8+ T cell population with an exhausted-like phenotype (CD45R0+PD-1+TBET+EOMES+) that was found in both anti–PD-1 and anti–CLTLA-4 treated patients. Furthermore, a TH1-like CD4 T cell population (CD45RO+ICOS+PD-1loTBET) was expanded only in anti–CTLA-4–treated tumors. These ICB responding T cell populations in the patients were very similar to those in the murine tumor models. The results suggest that the antitumor effects of targeting CTLA-4 or PD-1 are at least in part mediated by distinct cellular mechanisms, and these differences are seen across tumor types. Future work is needed to determine the importance of the CD4+ T cells responses unique to anti–CTLA-4 therapy and whether same T cell subset responses are associated with complete tumor rejection. It will also be of interest to analyze both tumor and blood samples from the same ICB treated patients.

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