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

Abstract

Immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment providing unprecedented clinical benefits. However, many patients do not respond to ICIs as monotherapy or develop resistance. Combining ICI-based immunotherapy with chemotherapy is a promising strategy to increase response rates, but few rationale-driven chemo-immunotherapy combinations have reached the clinical arena thus far. In the present study, we show that combined anti-PDL1 and anti-PDL2 antibodies optimally synergize with cyclophosphamide but not with cisplatin, and that the magnitude and duration of the therapeutic response is dependent on the immunogenic potential of the drug and of the tumor itself. Hallmarks of successful therapeutic outcomes were the enhanced infiltration by myeloid (mainly cross-presenting dendritic cells, eosinophils, and monocytic myeloid cells) and T lymphocytes into the tumor tissue and the expansion of circulating memory pools. Overall, our results suggest that immunomodulating chemotherapy can be exploited to increase the efficacy of PD1/PDL axis inhibitors in vivo, and that the magnitude of the synergic therapeutic response is affected by tumor-intrinsic immunogenicity.

Anticancer Effects of Sublingual Type I IFN in Combination with Chemotherapy in Implantable and Spontaneous Tumor Models

“…Nevertheless, pixel-by-pixel analyses over entire lesions (whole-lesion analyses) showed sharper peak (increased kurtosis) in both ADC and perfusion component histogram 96 h after treatment ( Supplementary Figure S1B,C ), indicating more homogeneous tumors after treatment. The analysis of tumor infiltrate revealed the increased frequency of CD19 + lymphocytes and, among myeloid cells, of putative M-MDSC and DC into the tumor bed 96 h after CTX treatment ( Supplementary Figure S1D,E ), as previously reported [ 50 ].…”

“…One group of mice received four doses of Sl-IFN, without CTX pretreatment, and another group was injected with saline as control. Treatment with a single injection of CTX + Sl-mock induced a transient reduction in tumor size ( Figure 5 B) similar to what was observed in other tumor models ( Figure 3 E and [ 50 , 51 , 54 ]).…”

“…Since previous data from our group demonstrated a synergistic anticancer effect of parenteral IFN-I and some anticancer drugs, such as cyclophosphamide (CTX), cis-diamminedichloroplatinum (II) (CDDP) and epigenetic compounds [ 29 , 46 , 50 , 51 ], we aimed to evaluate whether Sl-IFN is also effective when combined with these drugs in tumor-bearing mice. Thus, C57Bl/6 female mice were implanted subcutaneously (s.c.) in the right flank with either B16-OVA melanoma cells or with EG.7-OVA lymphoma cells.…”

Update Breast Cancer 2020 Part 5 – Moving Therapies From Advanced to Early Breast Cancer Patients

“…Ultimately, however, such an explanation must be regarded as speculative. It is known that different chemotherapies have different effects on the immune system 33 and also interact differently with PD1/PD-L1 inhibitors 34 .…”

“…Letztendlich ist eine Erklärung jedoch spekulativ. Es ist bekannt, dass unterschiedliche Chemotherapien einen unterschiedlichen Einfluss auf das Immunsystem haben 33 und auch unterschiedlich mit PD1/PD-L1-Inhibitoren interagieren 34 .…”