Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade

Abstract

SUMMARYImmune checkpoint blockade therapies fail to induce responses in majority of cancer patients; so how to increase the objective response rate becomes an urgent challenge. Here we demonstrate that sufficient T cell infiltration in tumor tissues is a prerequisite for response to PD-L1 blockade. Targeting tumors with tumor necrosis factor superfamily member LIGHT activates lymphotoxin beta receptor signaling, leading to the production of chemokines that recruit massive numbers of T cells. Furthermore, targeting non-T cell-inflamed tumor tissues by antibody-guided LIGHT creates a T cell-inflamed microenvironment and overcomes tumor resistance to checkpoint blockade. Our data indicates that targeting LIGHT might be a potent strategy to increase the responses to checkpoint blockades and other immunotherapies in non-T cell-inflamed tumors.

Tumor-TargetingSalmonella typhimuriumA1-R Sensitizes Melanoma With a BRAF-V600E Mutation to Vemurafenib in a Patient-Derived Orthotopic Xenograft (PDOX) Nude Mouse Model

“…Despite progress in melanoma therapy, there is still no cure for stage III and IV disease due to drug resistance, tumor heterogeneity and an immunosuppressive tumor environment [Brożyna et al, ; Chapman et al, ; Flaherty et al, ; Slominski and Carlson, ; Tang et al, ]. In addition, the presence of melanin appears to interfere with chemotherapy and radiotherapy of this recalcitrant disease [Brożyna et al, ].…”

“…Recently‐developed immuno‐therapy for melanoma has not significantly increased the 5‐year survival rate [Gandini et al, ]. The chemotherapy drugs, dacarbazine, and cisplatinum have had limited efficacy on melanoma [Rabik and Dolan, ; Tang et al, ]. Vemurafenib (VEM), a tyrosine kinase inhibitor targets BRAF‐V600E kinase, has had efficacy on BRAF‐V600E‐mutant melanoma [Chapman et al, ; Larkin et al, ; McArthur et al, ; Sosman et al, ].…”

NGR-hTNF and Doxorubicin as Second-Line Treatment of Patients with Small Cell Lung Cancer

“…In this regard, the drug ability to increase the intratumoral T‐cell infiltration , a prerequisite for response to immune checkpoint blockade , should facilitate the combination of NGR‐hTNF with immune checkpoint inhibitors, to be evaluated in a randomized phase II setting.…”

“…Finally, the mechanism of action of NGR‐hTNF, which increases the intratumoral lymphocyte infiltration , might facilitate its combination with immune checkpoint inhibitors, which require high levels of tumor‐infiltrating lymphocytes , with benefit to be assessed in a randomized phase II setting.…”

Immune profiles of desmoplastic small round cell tumor and synovial sarcoma suggest different immunotherapeutic susceptibility upfront compared to relapse specimens

“…described the combination of CD8 + cellular infiltrates and CD45RO + cellular infiltrates to formulate a prognostically significant “immunoscore” in colon cancer . In fact, naturally occurring tumor‐infiltrating lymphocytes have been associated with better patient survival in numerous cancer types and may also correlate with better responsiveness to checkpoint inhibition …”