Immuno-oncology

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Identification of Unconventional Immunosuppressive cd4+foxp3-pd-1hi T Cells as a Biomarker of Immune Checkpoint Blockade Activity

Friday, June 16
6:15 PM - 7:30 PM

Despite the clinical successes of immune checkpoint blockade, a significant proportion of cancer patients relapse or are refractory to this intervention. This underscores the need to better clarify the biologic activity of checkpoint blockade and identify effective biomarkers for improving patients’ selection and utilization of these strategies. Here, we aimed to determine the biologic and therapeutic significance of modulation of CD4+Foxp3-PD1hi T cells (abbreviated as 4PD1hi) during immune checkpoint blockade. We found that anti-CTLA-4 increased intratumoral and peripheral 4PD1hi in a dose-dependent manner, while combination with anti-PD-1 mitigated this effect and significantly improved anti-tumor activity. Furthermore, on-treatment increases in 4PD1hi during PD-1 blockade were associated with a poor prognosis in cancer patients, pointing to 4PD1hi as a potential resistance mechanism. 4PD1hi accumulated intratumorally as a function of tumor growth in untreated mice. Functional analyses revealed that both mouse and human circulating and intra-tumor 4PD1hi suppressed T-cell activation in a PD-1/PD-L1 dependent fashion. In addition, 4PD1hi from naïve and tumor-bearing hosts (mice and humans) resembled follicular-helper-T-cell(TFH)-like cells. Accordingly, immunization with sheep red blood cells increased this unconventional suppressive T-cell pool, while Bcl6 inhibition exerted the opposite effect and delayed tumor growth selectively in immune competent mice. These findings indicate that disinhibited T-cell priming promoted by anti-CTLA-4 may boost immunosuppressive 4PD1hi with TFH-like features in a dose dependent manner, and PD-1 blockade can counteract this effect. This contributes to understanding the incremental activity of combination checkpoint blockade and provides a new pharmacodynamic and prognostic biomarker for the design of optimal combination schedules.

Roberta Zappasodi

Research Scholar
Parker Institute for Cancer Immunotherapy, Ludwig Collaborative and Swim Across America laboratory, Memorial Sloan Kettering Cancer Center

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    Sadna Budhu

    Ludwig Collaborative and Swim Across America laboratory, Memorial Sloan Kettering Cancer Center

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      Matthew D. Hellmann

      Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center

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        Michael Postow

        Memorial Sloan Kettering Cancer Center

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          Yasin Senbabaoglu

          Memorial Sloan Kettering Cancer Center

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            Yanyun Li

            Memorial Sloan Kettering Cancer Center

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              Cailian Liu

              Ludwig Collaborative and Swim Across America laboratory, Memorial Sloan Kettering Cancer Center

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                Hong Zhong

                Ludwig Collaborative and Swim Across America laboratory, Memorial Sloan Kettering Cancer Center

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                  Billel Gasmi

                  Ludwig Collaborative and Swim Across America laboratory, Memorial Sloan Kettering Cancer Center

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                    Daniel Hirschhorn Cymerman

                    Ludwig Collaborative and Swim Across America laboratory, Memorial Sloan Kettering Cancer Center

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                      Katherine S. Panageas

                      Memorial Sloan Kettering Cancer Center

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                        Merghoub Taha

                        Assistant Member
                        Parker Institute for Cancer Immunotherapy, Ludwig Collaborative and Swim Across America laboratory, Memorial Sloan Kettering Cancer Center

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                          Jedd D. Wolchok

                          Parker Institute for Cancer Immunotherapy, Ludwig Collaborative and Swim Across America laboratory, Memorial Sloan Kettering Cancer Center

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                            Identification of Unconventional Immunosuppressive cd4+foxp3-pd-1hi T Cells as a Biomarker of Immune Checkpoint Blockade Activity



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