Suppression of Type I IFN Signaling in Tumors Mediates Resistance to Anti-PD-1 Treatment That Can Be Overcome by Radiotherapy

Abstract

Immune checkpoint therapies exhibit impressive efficacy in some patients with melanoma or lung cancer, but the lack of response in most cases presses the question of how general efficacy can be improved. In addressing this question, we generated a preclinical tumor model to study anti-PD-1 resistance by in vivo passaging of Kras-mutated, p53-deficient murine lung cancer cells (p53R172HΔg/+K-rasLA1/+) in a syngeneic host exposed to repetitive dosing with anti-mouse PD-1 antibodies. PDL1 (CD274) expression did not differ between the resistant and parental tumor cells. However the expression of important molecules in the antigen presentation pathway, including major histocompatibility complex (MHC) class I and II, as well as β2-microglobulin were significantly downregulated in the anti-PD1-resistant tumors compared with parental tumors. Resistant tumors also contained fewer CD8+ (CD8α) and CD4+ tumor-infiltrating lymphocytes (TILs) and reduced production of interferon-γ (IFN-γ). Localized radiotherapy induced IFN-β production, thereby elevating MHC class I expression on both parental and resistant tumor cells and restoring the responsiveness of resistant tumors to anti-PD1 therapy. Conversely, blockade of type I IFN signaling abolished the effect of radiosensitization in this setting. Collectively, these results identify a mechanism of PD1 resistance and demonstrate that adjuvant radiation therapy can overcome resistance. These findings have immediate clinical implications for extending the efficacy of anti-PD-1 immune checkpoint therapy in patients.

Dinaciclib induces immunogenic cell death and enhances anti-PD1–mediated tumor suppression

“…Type I IFN promotes antigen presentation and priming of antitumor T cells, and expression of type I IFN genes has been linked to positive prognosis in response to chemotherapy and radiation (30,59,60). ICD-inducing agents, including anthracyclines, radiation therapy, and oncolytic viruses, have been shown to upregulate type I IFN response genes within the tumor cell (30,50,(60)(61)(62)(63)(64). Induction of the type I IFN response can be protective in preclinical tumor models, and combination treatment with anti-PD1 has been shown to significantly prolong survival over monotherapy (65,53).…”

“…Induction of the type I IFN response can be protective in preclinical tumor models, and combination treatment with anti-PD1 has been shown to significantly prolong survival over monotherapy (65,53). Recently, induction of a type I IFN response via radiation therapy was shown to overcome tumor resistance to anti-PD1 (64). However, persistent type I IFN signaling can be immunosuppressive and lead to checkpoint blockade resistance (52).…”

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

“…21 The increased expression of MHC I molecules could also be linked to the increased type I IFN responses. 35 Importantly, resistance to anti-PD1 therapy could be mediated by suppression of type I IFN signaling in a preclinical model of Kras-mutated p53-deficient lung cancer. 35 In this model, induction of IFNβ by radiotherapy was able to elevate MHC I expression and restore the responsiveness of resistant tumors to anti-PD1 therapy.…”

“…35 Importantly, resistance to anti-PD1 therapy could be mediated by suppression of type I IFN signaling in a preclinical model of Kras-mutated p53-deficient lung cancer. 35 In this model, induction of IFNβ by radiotherapy was able to elevate MHC I expression and restore the responsiveness of resistant tumors to anti-PD1 therapy. Increased FAS expression with SGT-53 treatment could also increase CTL-mediated apoptosis of tumor cells since CTLs use FAS/FAS ligand binding to induce apoptosis of target cells during the CTL-tumor cell interaction.…”

Radio-Immunotherapy: A Promising Weapon to Consider in the Fight against NSCLC

“…Other effects provoked by radiation include increased expression of NKG2D ligands and sensitivity to NK cell-mediated cytotoxicity of tumor cells 15 and radiation-induced type I interferon (IFN) production, upregulated MHC class I expression, and restored response to anti-PD-1 in anti-PD-1-resistant rat models. 16 These molecular mechanisms open the possibility of a synergistic effect when used in conjunction with immunotherapy. …”