Shayna Thomas-Jardin

We identified an important oncogenic role for protocadherin 7 (PCDH7), a cell surface protein frequently overexpressed in lung adenocarcinoma and associated with poor clinical outcome. Pcdh7 depletion reduces tumor burden and prolongs survival in Kras ^LSL-G12D ; Tp53 ^fl/fl mice. These findings nominate this cell surface protein as an actionable therapeutic target and highlight the therapeutic potential of PCDH7 inhibition for non–small cell lung cancer. We report the development and characterization of high-affinity anti-PCDH7 monoclonal antibodies (mAbs) that inhibit downstream mitogen-activated protein kinase (MAPK) pathway activation and suppress tumor growth in multiple mutant KRAS –driven models. A lead mAb (mAb7) sensitized tumors to the US Food and Drug Administration–approved MAPK kinase inhibitor trametinib and the KRAS ^G12C inhibitor adagrasib. A humanized mAb7-IgG1 (Hu-mAb7) exhibited antibody-dependent cellular cytotoxicity and Fc-mediated immune effector killing of tumor cells in vivo. Moreover, a murinized antibody (Ms-mAb7) improved antitumor immunity in a Kras ^G12D syngeneic tumor model by enhancing infiltration and activation of cytotoxic immune cells. These findings provide an important advance in the clinical development of PCDH7-targeting antibodies for lung cancer treatment.

Supplementary Figure 3 shows the effect of ISR pathway activation on dendritic cells and T cells.

Supplementary Table 4 shows the clinicopathological characteristics of surgically resected primary NSCLC patients included in this study.

Supplementary Figure 5 shows the effect of ISR pathway inhibition on immune cell populations in vivo.

Supplementary Figure 2 shows the effect of ISR pathway activation on protein and mRNA stability, and translation.

Supplementary Table 2 shows the primers used in this study.

Supplementary Figure 4 shows the effect of ISR pathway inhibition in vitro and in vivo.

The integrated stress response (ISR) is an adaptive pathway hijacked by cancer cells to survive cellular stresses in the tumor microenvironment. ISR activation potently induces PD-L1, leading to suppression of antitumor immunity. In this study, we sought to uncover additional immune checkpoint proteins regulated by the ISR to elucidate mechanisms of tumor immune escape. The ISR coordinately induced cluster of differentiation 155 (CD155) and PD-L1, enhancing translation of both immune checkpoint proteins through bypass of inhibitory upstream open reading frames in their 5′ untranslated regions. Analysis of primary human lung tumors identified a significant correlation between expression of PD-L1 and CD155. ISR activation accelerated tumorigenesis and inhibited T-cell function, which could be overcome by combining PD-1 and TIGIT blockade with the ISR inhibitor ISRIB. This study uncovers a mechanism by which two immune checkpoint proteins are coordinately regulated and suggests a therapeutic strategy for patients with lung cancer.Significance:The integrated stress response represents a targetable axis to improve the efficacy of immunotherapy in lung cancer by inhibiting the coordinated translational regulation of the PD-L1/PD-1 and CD155/TIGIT immune checkpoint pathways.

Supplementary Table 1 shows the chemicals used in this study.

Supplementary Table 3 shows the antibodies used in this study.