AI Article Synopsis
- A notable number of patients treated with anti-PD1 antibodies do not respond, prompting research using mouse models to investigate this issue.
- The study found that the levels of T-cell PD1 and myeloid PDL1 in tumors relate inversely and influence how well anti-PD1 therapy works, particularly affecting the function of CD8(+) T cells.
- Tumors that respond to treatment show a specific threshold for PD1 downregulation on CD8(+) T cells, while those that don't respond often have dysfunctional PD1(hi) T cells that need targeting of PDL1(lo) immune cells to overcome resistance.
Article Abstract
Despite successes, thus far, a significant proportion of the patients treated with anti-PD1 antibodies have failed to respond. We use mouse tumor models of anti-PD1 sensitivity and resistance and flow cytometry to assess tumor-infiltrating immune cells immediately after therapy. We demonstrate that the expression levels of T-cell PD1 (PD1(lo)), myeloid, and T-cell PDL1 (PDL1(hi)) in the tumor microenvironment inversely correlate and dictate the efficacy of anti-PD1 mAb and function of intratumor CD8(+) T cells. In sensitive tumors, we reveal a threshold for PD1 downregulation on tumor-infiltrating CD8(+) T cells below which the release of adaptive immune resistance is achieved. In contrast, PD1(hi) T cells in resistant tumors fail to be rescued by anti-PD1 therapy and remain dysfunctional unless intratumor PDL1(lo) immune cells are targeted. Intratumor Tregs are partly responsible for the development of anti-PD1-resistant tumors and PD1(hi) CD8(+) T cells. Our analyses provide a framework to interrogate intratumor CD8(+) T-cell PD1 and immune PDL1 levels and response in human cancer.
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| http://dx.doi.org/10.1158/0008-5472.CAN-15-1082 | DOI Listing |
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