Tissue Injury and Biomaterial Treatment Modulate Tumor Growth and Response to Immunotherapy

Abstract Immunotherapies have transformed cancer care; however, tumor intrinsic and extrinsic factors contribute to high variability in therapeutic responses. While tissue injuries can impact cancer recurrence and metastatic spread, little is known about their potential to effect immune checkpoint blockade (ICB) response. In this study, we reveal that distal traumatic muscle injury accelerated progression and impaired adjuvant ICB response of multiple murine tumors. This injury-induced accelerated tumor growth coincided with decreased intra-tumoral density and effector phenotype of tumor-reactive CD8+ T cells and relied on communication through a shared draining lymph node. Enhancing injury repair using a biological scaffold abrogated the injury-induced accelerated tumor growth in an interleukin-4-dependent manner and improved ICB response. In a retrospective cohort analysis of breast cancer patients undergoing ICB treatment, biological scaffold implantation following mastectomy was associated with increased overall survival. This work suggests that injury-driven immune dysfunction may contribute to cancer progression and ICB resistance, but enhancing wound healing with pro-regenerative biomaterials may offer a viable strategy for mitigating adverse cancer outcomes, particularly in the setting of adjuvant and neoadjuvant ICB. Competing Interest Statement A.R. is an independent contractor for Aegeria Soft Tissue. C.C. is the owner of C M Cherry Consulting. K.N.S holds founders equity in Clasp Therapeutics. D.M.P. is a consultant at Aduro Biotech, Amgen, Astra Zeneca, Bayer, Compugen, DNAtrix, Dynavax Technologies Corporation, Ervaxx, FLX Bio, Immunomic, Janssen, Merck, and Rock Springs Capital. D.M.P. holds equity in Aduro Biotech, DNAtrix, Ervaxx, Five Prime therapeutics, Immunomic, Potenza, Trieza Therapeutics. D.M.P. is a member of the scientific advisory board for Bristol Myers Squibb, Camden Nexus II, Five Prime Therapeutics, and WindMil. D.M.P. is a member of the board of directors in Dracen Pharmaceuticals. J.H.E. holds equity in Unity Biotechnology and Aegeria Soft Tissue and is a consultant for Tessara.