Combined Inhibition of SHP2 and CXCR1/2 Promotes Anti-Tumor T Cell Response in NSCLC

Tang, K. H.; Li, S.; Khodadadi-Jamayran, A.; Jen, J.; Han, H.; Guidry, K.; Chen, T.; Hao, Y.; Fedele, C.; Zebala, J.; Maeda, D.; Christensen, J.; Olson, P.; Athanas, A.; Wong, K.-K.; Neel, B. G.

doi:10.1101/2021.03.21.436338

bioRxiv · 10.1101/2021.03.21.436338

Combined Inhibition of SHP2 and CXCR1/2 Promotes Anti-Tumor T Cell Response in NSCLC

Tang, K. H.·Li, S.·Khodadadi-Jamayran, A.·Jen, J.·Han, H.·Guidry, K.·Chen, T.·Hao, Y.·Fedele, C.·Zebala, J.·Maeda, D.·Christensen, J.·Olson, P.·Athanas, A.·Wong, K.-K.·Neel, B. G.

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Abstract

Clinical trials of SHP2 inhibitors (SHP2i) alone and in various combinations are ongoing for multiple tumors with over-activation of the RAS/ERK pathway. SHP2 plays critical roles in normal cell signaling; hence, SHP2is could influence the tumor microenvironment. We found that SHP2i treatment depleted alveolar and M2-like macrophages and promoted B and T lymphocyte infiltration in Kras- and Egfr-mutant non-small cell lung cancer (NSCLC). However, treatment also increased intratumor gMDSCs via tumor-intrinsic, NF-kB-dependent production of CXCR2 ligands. Other RAS/ERK pathway inhibitors also induced CXCR2 ligands and gMDSC influx in mice, and CXCR2 ligands were induced in tumors from patients on KRASG12C-inhibitor trials. Combined SHP2(SHP099)/CXCR1/2(SX682) inhibition depleted a specific cluster of S100a8/9high gMDSCs, generated Klrg1+ CD8+ effector T cells with a strong cytotoxic phenotype but expressing the checkpoint receptor NKG2A, and enhanced survival in Kras-and Egfr-mutant models. Our results argue for testing RAS/ERK pathway/CXCR1/2/NKG2A inhibitor combinations in NSCLC patients. Statement of SignificanceOur study shows that inhibiting the SHP2/RAS/ERK pathway triggers NF-kB-dependent up-regulation of CXCR2 ligands and recruitment of S100A8high gMDSCs, which suppress T cells in NSCLC. Combining SHP2 and CXCR2 inhibitors blocks this gMDSC immigration, resulting in enhanced Th1 polarization, induction of CD8+ KLRG1+ effector T cells with high cytotoxic activity and improved survival in multiple NSCLC models.

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Tang, K. H., Li, S., Khodadadi-Jamayran, A., Jen, J., Han, H., Guidry, K., Chen, T., Hao, Y., Fedele, C., Zebala, J., Maeda, D., Christensen, J., Olson, P., Athanas, A., Wong, K.-K., Neel, B. G.. 2021-03-21. Combined Inhibition of SHP2 and CXCR1/2 Promotes Anti-Tumor T Cell Response in NSCLC. https://doi.org/10.1101/2021.03.21.436338

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