MCL1 inhibition targets Myeloid Derived Suppressors Cells, promotes antitumor immunity and enhances the efficacy of immune checkpoint blockade.

Immune checkpoint inhibitors (ICIs) are now the first-line treatment for patients with advanced melanoma. Despite promising clinical results, many patients fail to respond to these therapies. BH3 mimetics, a novel class of small molecule inhibitors that bind and inhibit anti-apoptotic members of the BCL2 family proteins such as BCL2 or MCL1, have been very successful in treating hematologic malignancies.

Dysfunctional states of unconventional T-cell subsets in cancer.

Unconventional T cells represent a promising therapeutic agent to overcome the current limitations of immunotherapies due to their universal T-cell receptors, ability to respond directly to cytokine stimulation, and capacity to recruit and modulate conventional immune cells in the tumor microenvironment. Like conventional T cells, unconventional T cells can enter a dysfunctional state, and the functional differences associated with this state may provide insight into the discrepancies observed in their role in antitumor immunity in various cancers. The exhaustive signature of unconventional T cells differs from conventional αβ T cells, and understanding the differences in the mechanisms underlying exhaustive differentiation in these cell types may aid in the discovery of new treatments to improve sustained antitumor responses.

Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity.

Lysophosphatidic acid (LPA) is a bioactive lipid which increases in concentration locally and systemically across different cancer types. Yet, the exact mechanism(s) of how LPA affects CD8 T cell immunosurveillance during tumor progression remain unknown. We show LPA receptor (LPAR) signaling by CD8 T cells promotes tolerogenic states via metabolic reprogramming and potentiating exhaustive-like differentiation to modulate anti-tumor immunity.

Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma.

Purpose: A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma.

Patients And Methods: Anti-PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination.