Cancer-induced nerve injury promotes resistance to anti-PD-1 therapy [RNA-Seq FFPE]

Peri-neural invasion (PNI) is a well-established poor prognostic factor in multiple cancer types. However, the mechanisms driving the PNI's detrimental clinical effect remain elusive. Here, we provide clinical and mechanistic insights into PNI and cancer-induced injury of tumor-associated nerves (TANs) and their role in resistance to anti-PD-1 therapy. Our work demonstrates that poor response to anti-PD-1 therapy in cutaneous squamous cell carcinoma (cSCC), melanoma, and gastric cancer is associated with PNI and TANs injury. Ultrastructural electron microscopy analysis reveals that direct contact between cancer cells and nerve fibers leads to cancer-induced nerve injury (CINI) via myelin degradation. Injured neurons respond by autonomously initiating an interleukin (IL)-6 and interferon (IFN) type I inflammatory response. This inflammatory response alters the immune activity in the peri-neural niche in melanoma, cSCC, and pancreatic adenocarcinoma, leading to an immuno-suppressive activity aimed at nerve healing and regeneration. As the tumor grows, the CINI burden increases, the inflammatory signal within the niche becomes chronic, and eventually skews the general immune tone within the tumor microenvironment to a suppressive and exhaustive state. The CINI-driven anti-PD-1 resistance can be reversed by targeting multiple steps in the CINI signaling process: denervating the tumor, conditional knockout of the transcription factor mediating the injury signal within neurons (cKO-Atf3), knockout of the IFN-a receptor signaling (Ifnar1-/-), or by combining anti-PD-1 and anti-IL-6-receptor blockade. Our findings demonstrate the direct immuno-regulatory roles of TANs and their therapeutic potential. The study protocol of the clinical trial is available online (NCT04154943). This manuscript reports patients enrolled in the University of Texas MD Anderson Cancer Center (Houston, Texas, USA) and Moffitt Cancer Center (Tampa, Florida, USA). After a screening period of up to 28 days, patients received neoadjuvant cemiplimab 350 mg intravenously every 3 weeks until unacceptable toxicity, disease progression, or withdrawal of consent. After completion of neoadjuvant treatment, the protocol window for surgery was study days 75–100. If the patient met the criteria for early discontinuation of cemiplimab during the neoadjuvant period, the treating physician could divert the patient to surgery earlier. Pretreatment biopsy specimens were subjected to histopathologic assessment for confirmation of diagnosis and to permit morphologic comparison between tumor tissue before treatment and any residual tumor following therapy. Pathologic response was assessed in the posttreatment surgical specimens according to standard pathologic evaluation recommendations 2 and re-reviewed by a dedicated dermatopathologist (PN) to standardize reporting. The primary endpoint was pathologic complete response (pCR), defined as the absence of viable tumor in post-treatment surgical specimens, determined per independent central pathology review. Major pathologic response (MPR) was a secondary endpoint defined by the presence of >0% but ≤10% viable tumor cells in post-treatment surgical specimens.