Sustained Type I interferon signaling as a mechanism of resistance to PD-1 blockade

Abstract

PD-1 blockade represents a major therapeutic avenue in anticancer immunotherapy. Delineating mechanisms of secondary resistance to this strategy is increasingly important. Here, we identified the deleterious role of signaling via the type I interferon (IFN) receptor in tumor and antigen presenting cells, that induced the expression of nitric oxide synthase 2 (NOS2), associated with intratumor accumulation of regulatory T cells (Treg) and myeloid cells and acquired resistance to anti-PD-1 monoclonal antibody (mAb). Sustained IFNβ transcription was observed in resistant tumors, in turn inducing PD-L1 and NOS2 expression in both tumor and dendritic cells (DC). Whereas PD-L1 was not involved in secondary resistance to anti-PD-1 mAb, pharmacological or genetic inhibition of NOS2 maintained long-term control of tumors by PD-1 blockade, through reduction of Treg and DC activation. Resistance to immunotherapies, including anti-PD-1 mAb in melanoma patients, was also correlated with the induction of a type I IFN signature. Hence, the role of type I IFN in response to PD-1 blockade should be revisited as sustained type I IFN signaling may contribute to resistance to therapy.

Development of an IFNγ response‐related signature for predicting the survival of cutaneous melanoma

“…However, the onset of and proclivity to the development of treatment‐based resistance and of recurrence of SKCM also persist. It has been estimated that approximately 60%‐80% patients receiving these treatments get no satisfying prognosis or lasting response 36,37 . Thus, SKCM is greatly suppressive and straightforwardly involved in immune evasion, which relies upon the interplay of SKCM cells with immune cells existing in the TME.…”

Dual blockade of IL-6 and CTLA-4 regresses pancreatic tumors in a CD4+T cell-dependent manner

“…Targeting select cytokines, such as IL-6, has the unique potential to shift the overall immune response in a manner which alters Th1/Th2/Th17 cytokine balance that may be aberrantly regulated in advanced malignancy. In essence, this dysregulated cytokine balance can lead to 1) direct inhibition of cytotoxic effector cell function; 2) expansion of immune suppressive lymphoid and myeloid cell populations; 3) reciprocal activation of pro-oncogenic and prometastatic pathways in the tumor cells (16,(20)(21)(22)(31)(32)(33)(34). In the setting of PDAC, the stroma contributes significantly to the production of tumor-promoting cytokines and chemokines.…”

Tumor-Intrinsic or Drug-Induced Immunogenicity Dictates the Therapeutic Success of the PD1/PDL Axis Blockade

“…Mechanism of acquired resistance have also been reported, including IFNγ-induced upregulation of PDL1 [1,12] and TCR-dependent upregulation of additional exhaustion markers on T cells such as T lymphocytes, including T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), and lymphocyte activation gene 3 (Lag-3) [13]. Recently, sustained interferon (IFN)-αβ signaling has also been associated to secondary resistance to anti-PD1 therapy [14].…”