Core Support for Cancer Center

Albert Einstein College Of Medicine, Bronx NY

Investigators

Linked publications, trials & patents

Abstract

As monotherapy, the clinical benefit of PD-1/PD-L1 inhibitor appears to be restricted to about 15-20% of unselected lung cancer patients, many of them with a high expression of PD-L1, thus suggesting a non-PD1/PD-L1 based mechanisms of immune evasion. HHLA2, B7x and B7-H3 are recently discovered members of the immune checkpoint B7/CD28 family. The tolerability and efficacy of immunotherapy remains largely unknown in people living with HIV (PLWH) on ART, who had generally been excluded from previous trials. We found that B7x, B7-H3 and HHLA2 were widely expressed in general lung cancers and all inhibited T cell functions. The majority of PD-L1 negative tumors expressed B7x, HHLA2 or both. Our preliminary data revealed a remarkably low frequency and intensity of PD-L1 expression in PLWH and lung cancer, implicating that non-PD-1/PD-L1 mediated immune evasion may play key roles in this setting. We hypothesize that by regulating T-cell functions, the new and commonly expressed immune checkpoint molecules may constitute clinically relevant alternative mechanisms of immune evasion and thus novel targets for immunotherapy in PLWH with lung cancer. Aim 1: To characterize the expression profiles and prognostic implications of PD- L1 and novel immune checkpoints (HHLA2, B7x and B7H3) in PLWH with lung cancer. Using a unique collection of PLWH with lung cancer, we will determine the expression profiles of above immune checkpoint molecules by IHC and MQIF. We will also assess the expression profiles of these immune checkpoints in patients receiving anti-PD-1/PD-L1 treatment to evaluate their roles in mediating resistance to PD-1/PD-L1 inhibitors. Aim 2: To characterize the expression profile and prognostic implication of tumor infiltrating lymphocytes (TILs), TCR repertoire clonality, and neoantigen pattern in PLWH with lung cancer. We hypothesize that the genetic and immune landscapes may be unique in PLWH with lung cancer (and different from general lung cancer patients). To test this hypothesis, we will determine TILs (IHC and MQIF), neoantigen pattern (WES and RNA sequencing) and TCR repertoire (immuno-sequencing) in these patients. We will determine the association between TILs, TCR clonality, neoantigen burden and clinico-pathological characteristics. Expected outcome and Impact: The proposed work is likely establishing the clinical relevance of the expression and function of novel immune checkpoint molecules in PLWH with lung