Both anti–PD-1 and anti-CTLA4 target subpopulations of exhausted-like CD8+ T cells.

  • Major finding: Both anti–PD-1 and anti-CTLA4 target subpopulations of exhausted-like CD8+ T cells.

  • Mechanism: Anti-CTLA4 promotes expansion of an ICOS+TBET+ Th1-like CD4+ T-cell effector subset.

  • Impact: Anti-CTLA4 and anti–PD-1 act through distinct cellular mechanisms to promote tumor rejection.

Immune checkpoint blockade (ICB) with anti-CTLA4 or anti–PD-1 antibodies achieves durable responses in a minority of patients with cancer. A better understanding of the mechanisms by which ICB promotes tumor rejection may lead to improved therapeutic strategies. Wei and colleagues sought to determine if anti-CTLA4 and anti–PD-1 mediate antitumor immune responses through distinct, nonredundant mechanisms using mass cytometry of tumor-infiltrating lymphocytes from MC38 colorectal tumors from mice treated with anti-CTLA4 or anti–PD-1. ICB with anti-CTLA4 or anti–PD-1 resulted in expansion of specific intratumoral CD8+ T-cell subsets, with the exhausted PD-1hiTIM3+ population expanding the most following ICB. Anti-CTLA4 treatment promoted specific expansion of an ICOS+TBET+ Th1-like CD4+ effector subset, but anti–PD-1 did not, indicating that anti–PD-1 and anti-CTLA4 target distinct T-cell populations. Similar results were observed in the poorly immunogenic B16BL6 melanoma model, suggesting that the mechanisms underlying the response to ICB are independent of tumor type. Further, gene expression analysis revealed that anti-CTLA4 and anti–PD-1 altered expression of largely nonoverlapping sets of genes, consistent with different mechanisms of action. To determine if these findings are relevant in patients with melanoma, a T-cell mass cytometry panel was used to analyze melanomas from patients treated with anti-CTLA4 (ipilimumab), anti–PD-1 (nivolumab or pembrolizumab), or the combination. Of 19 identified T-cell subsets, 2 were significantly expanded in ICB-treated tumors compared with normal blood, a subset analogous to the exhausted-like terminally differentiated CD8+ T-cell subset identified in mouse models and a CD4+ T-cell population analogous to the activated Th1-like effector subset in the mouse models. Anti-CTLA4, but not anti–PD-1, increased the frequency of Th1-like T cells, consistent with the mouse models. Collectively, these findings demonstrate that anti-CTLA4 and anti–PD-1 therapies act through different cellular mechanisms to promote antitumor immunity.

Wei SC, Levine JH, Cogdill AP, Zhao Y, Anang NA, Andrews MC, et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 2017 Aug 9 [Epub ahead of print].

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