Overcoming Genetically Based Resistance Mechanisms to PD-1 Blockade

Abstract

Mechanism-based strategies to overcome resistance to PD-1 blockade therapy are urgently needed. We developed genetic acquired resistant models of JAK1, JAK2, and B2M loss-of-function mutations by gene knockout in human and murine cell lines. Human melanoma cell lines with JAK1/2 knockout became insensitive to IFN-induced antitumor effects, while B2M knockout was no longer recognized by antigen-specific T cells and hence was resistant to cytotoxicity. All of these mutations led to resistance to anti-PD-1 therapy in vivo. JAK1/2-knockout resistance could be overcome with the activation of innate and adaptive immunity by intratumoral Toll-like receptor 9 agonist administration together with anti-PD-1, mediated by natural killer (NK) and CD8 T cells. B2Mknockout resistance could be overcome by NK-cell and CD4 T-cell activation using the CD122 preferential IL2 agonist bempegaldesleukin. Therefore, mechanistically designed combination therapies can overcome genetic resistance to PD-1 blockade therapy. SiGNifiCANCe:The activation of IFN signaling through pattern recognition receptors and the stimulation of NK cells overcome genetic mechanisms of resistance to PD-1 blockade therapy mediated through deficient IFN receptor and antigen presentation pathways. These approaches are being tested in the clinic to improve the antitumor activity of PD-1 blockade therapy.

Turning cold tumors into hot tumors by improving T-cell infiltration

“…B2M, the invariant chain of the MHC, is critical for the successful folding and transport of MHC-I to the cell surface 5 . Knocking down the B2M gene in the M202 and M233 human melanoma cell lines resulted in the absence of MHC-I molecules expressed on their surface, and the absence of tumor-specific T-cell recognition and cytotoxicity 24 . Identical results were observed in a B2M-knockout mouse model of lung cancer that showed resistance to PD-1 blockade 25 .…”

In vivo screens using a selective CRISPR antigen removal lentiviral vector system reveal immune dependencies in renal cell carcinoma

“…ll Resource beta-2-microglobulin (B2m) were strongly depleted in immunotherapy-treated Renca tumors, but not B16 tumors ( Figure 5D; FDR < 0.0001). The finding of enhanced sensitivity to immune checkpoint blockade after loss of B2m was unexpected, as B2m is required for MHC class I presentation and mutations in B2m have been previously associated with resistance to immune checkpoint blockade mediated by defective MHC antigen presentation (Zaretsky et al, 2016;Sade-Feldman et al, 2017;Torrejon et al, 2020).…”

Advances in identification and selection of personalized neoantigen/T-cell pairs for autologous adoptive T cell therapies

“… 112 Epitope spreading was, for example, observed when the APC growth factor Flt3L was introduced in adoptively transferred T cells. 113 Eventually, combinatorial therapies overcoming other resistance mechanisms such as PD-1 blockade 114 may also prove valuable in the ACT setting, and this is currently under investigation.…”