Addition of interleukin-2 overcomes resistance to neoadjuvant CTLA4 and PD1 blockade in ex vivo patient tumors

Abstract

Neoadjuvant immunotherapy with anti-cytotoxic T lymphocyte–associated protein 4 (CTLA4) + anti–programmed cell death protein 1 (PD1) monoclonal antibodies has demonstrated remarkable pathological responses and relapse-free survival in ~80% of patients with clinically detectable stage III melanoma. However, about 20% of the treated patients do not respond. In pretreatment biopsies of patients with melanoma, we found that resistance to neoadjuvant CTLA4 + PD1 blockade was associated with a low CD4/interleukin-2 (IL-2) gene signature. Ex vivo, addition of IL-2 to CTLA4 + PD1 blockade induced T cell activation and deep immunological responses in anti-CTLA4 + anti-PD1–resistant human tumor specimens. In the 4T1.2 breast cancer mouse model of neoadjuvant immunotherapy, triple combination of anti-CTLA4 + anti-PD1 + IL-2 cured almost twice as many mice as compared with dual checkpoint inhibitor therapy. This improved efficacy was due to the expansion of tumor-specific CD8 + T cells and improved proinflammatory cytokine polyfunctionality of both CD4 + and CD8 + T effector cells and regulatory T cells. Depletion studies suggested that CD4 + T cells were critical for priming of CD8 + T cell immunity against 4T1.2 and helped in the expansion of tumor-specific CD8 + T cells early after neoadjuvant triple immunotherapy. Our results suggest that the addition of IL-2 can overcome resistance to neoadjuvant anti-CTLA4 + anti-PD1, providing the rationale for testing this combination as a neoadjuvant therapy in patients with early-stage cancer.

IL-5-producing CD4+ T cells and eosinophils cooperate to enhance response to immune checkpoint blockade in breast cancer

“…45 This platform allows interrogation of the early immunological response of human tumor tissues upon ex vivo ICB treatment (aPD1 and combined aPD1 + aCTLA4). Importantly, the observed ex vivo response (defined as described previously 45,46 ) correlates with the clinical response of the patient. 45 We assessed the protein levels of IL-5 upon ex vivo ICB stimulation in tumors of patients with different tumor types.…”

“…(G) Fold change in IL-5 secretion by PDTF treated ex vivo with aPD-1+aCTLA-4 (left) or aPD-1 (right) compared with untreated condition, measured by LEGENDplex, comparing PDTF-R (responders) and PDTF-NR (non-responders), defined as described previously. 45,46 Tumor samples were collected from surgical material of patients with various tumor types (see STAR Methods and Table S4). S4.…”

“…PDTF culture and stimulation PDTF cultures were performed as described previously. 45,46 Briefly, tumor samples were collected from surgical material of patients with renal cell carcinoma (anti-PD1+anti-CTLA-4 treated n = 1 & anti-PD1 treated n = 2), ovarian cancer (n = 4 & n = 1), melanoma (n = 7 & n = 5), non-small cell lung cancer (n = 1 & n = 3), and colorectal cancer (n = 0 & n = 1). Patient characteristics were described previously for samples stimulated with aPD-1 & aCTLA-4 46 and listed in Table S4 for samples stimulated with aPD-1.…”

A Review of Gut Microbiota‐Derived Metabolites in Tumor Progression and Cancer Therapy

“…[143][144][145] The pro-inflammatory cytokine IL-2 enhances the antitumor capacity of chimeric antigen receptor T cells, helping them to overcome the resistance to PD-1 and cytotoxic T lymphocyte antigen 4 (CTLA-4). [146,147] This is because the antitumor immune capacity of many cancer patients is in a "cold" state, and inflammation activates it. Thus, pro-inflammatory cytokines have dual functions.…”

Intracranial tumors elicit systemic sympathetic hyperactivity that limits immunotherapeutic responses

“…Historically, studies have reported diminished T cell reactivity, often demonstrating limited proliferative and cytokine responses [4][5][6]8,9,14,[16][17][18][19]24,26,27,[35][36][37][38][39][40][41] . More current techniques assess multiple cytokines simultaneously to address T cell "polyfunctionality", [42][43][44][45][46][47][48][49][50][51][52][53] which has been linked to outcomes in various tumor types [54][55][56] . We thus used a high-throughput, ELISA-based single-cell cytokine secretion assay to assess T cell polyfunctionality and compared systemic T cell function in the setting of both intracranial and peripheral tumors.…”