Targeting mitochondrial oxygen demand to overcome hypoxic immune privilege of NSCLC tumors

ABSTRACT
Non-small cell lung cancer (NSCLC) is a highly aggressive disease with dismal prognosis associated with high
rates of treatment resistance and disease recurrence. In the last decade, first line NSCLC treatment has been
substantially reinforced with the introduction of immunotherapy targeting immune checkpoints such as
programmed cell death 1 (PD-1) or its ligand PD-L1. PD-1/PD-L1 immune checkpoint blockade (ICB) shows very
promising clinical profile, yet long-term disease control occurs in less than 25% of NSCLC patients.
Understanding the mechanisms of treatment resistance is essential to address the dire need of introducing novel
synergistic therapies to target refractory disease in immune-privileged NSCLC tumors. Experimental evidence
shows that NSCLC tumors, belonging among the most hypoxic tumor types, display poor rates of immune cell
infiltration and impaired T cell effector function within the hypoxic tumor regions. This suggests that low oxygen
may contribute to the immune privilege and poor response to treatment in NSCLC. Interestingly, tumor hypoxia
has been associated with anti-cancer treatment resistance for decades, yet its role in clinical management of
NSCLC remains largely unexplored. Recent literature suggests that persistent antigenic stimulation of tumor-
infiltrating CD8+ T cells within the hypoxic tumor microenvironment (TME) induces T cell exhaustion,
a dysfunctional state characterized by progressive loss of T cell effector function. In the current K22 Transition
Career Development Award application, we propose to investigate the role of tumor hypoxia as a modulator of
immune privilege in murine NSCLC models. We have previously identified that mitochondrial inhibitor papaverine
(PPV) and its experimental derivative SMV-32 can reversibly elevate partial oxygen pressure in murine NSCLC
tumor models by up to 90%. Our preliminary data show that PPV or SMV-32-mediated TME reoxygenation prior
to delivering PD-1 ICB led to significant enhancement of tumor growth delay in mouse syngeneic NSCLC tumor
models, compared to PD-1 monotherapy. Repeated treatment with either drug alone did not affect tumor growth.
We also show that hypoxia leads to enrichment of dysfunctional CD8+ T cell populations in vitro and in vivo and
that reoxygenation promotes elevation of PD-1 ICB-responsive progenitor exhausted T cell population while
decreasing terminally exhausted T cell population. The overall goal of the K22 proposal is to elucidate the TME-
specific mechanisms of hypoxic immune privilege in NSCLC tumors and to gain advanced research experience
and professional development required for transition into a successful independent investigator.

Grant Number: 5K22CA282363-02
NIH Institute/Center: NIH
Principal Investigator: Martin Benej