Classification of current anticancer immunotherapies

During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches

Rapamycin Expands and Confers Resistance to Apoptosis of Human Inducible Regulatory T Cells (TRI)

The immunosuppressive drug Rapamycin (RAPA) has been shown to promote expansion of CD4 + IL-10 + natural human regulatory T cells (nTreg) in vitro and in vivo . RAPA effects on inducible Treg (Tri) are unknown, and this study explores in vitro responses of Tr1 to this drug. CD4 + CD25 neg T cells isolated from PBMC of normal donors were used to generate Tr1 cells. Expanded Tr1 cells were tested for surface markers, expression of survival proteins, resistance to apoptosis and the ability to suppress proliferation of autologous CD4 + CD25 neg responder T cells (RC) in functional assays. RAPA was found to promote the generation of human Tr1 cells from autologous CD4 + CD2S neg precursors in peripheral blood. Tr1 cells + RAPA mediated higher suppression (p<0.01) of RC proliferation than Tr1 cells cultured without RAPA. Tr1 cells + RAPA also expressed higher levels of FasL and granzyme B (p<0.002), produced more IL-10 and TGF-βl and were more resistant to activation-induced cell death (p<0.02). RAPA up-regulated expression of the Bcl-2 family anti-apoptotic proteins in Tri. In addition, stimulation of Tr1 by LPS + RAPA resulted in increased proliferation and resistance to apoptosis. RAPA favors in vitro generation of inducible human Treg (Tr1) from CD4 + CD25 neg precursor cells and significantly enhances their survival and suppressor functions

Small extracellular vesicles in pre-therapy plasma predict clinical outcome in non-small-cell lung cancer patients

The potential use of plasma-derived small extracellular vesicles (sEV) as predictors of response to therapy and clinical outcome in chemotherapy-naïve patients with non-small-cell lung cancer (NSCLC) was explored. sEV were isolated by size-exclusion chromatography from the plasma of 79 chemotherapy-naïve NSCLC patients and 12 healthy donors (HD). sEV were characterized with regard to protein content, particle size, counts by qNano, morphology by transmission electron microscopy, and molecular profiles by Western blots. PD-1 and PD-L1 expression on circulating immune cells was analysed by flow cytometry. Pre-treatment levels of total sEV protein (TEP) were correlated with overall (OS) and progression-free survival (PFS). The sEV numbers and protein levels were significantly elevated in the plasma of NSCLC patients compared to HD (p = 0.009 and 0.0001, respectively). Baseline TEP levels were higher in patients who developed progressive disease compared to patients with stable disease (p = 0.007 and 0.001, stage III and IV, respectively). Patient-derived sEV were enriched in immunosuppressive proteins as compared to proteins carried by sEV from HD. TEP levels were positively correlated with CD8+PD-1+ and CD8+PD-L1+ circulating T cell percentages and were independently associated with poorer PFS (p &amp;lt; 0.00001) and OS (p &amp;lt; 0.00001). Pre-therapy sEV could be useful as non-invasive biomarkers of response to therapy and clinical outcome in NSCLC. © 2021 by the authors. Licensee MDPI, Basel, Switzerland