Significance: Anthracyclines like doxorubicin are anticancer drugs, used by over 1 million cancer patients annually. However, they cause severe side effects, most notably, cardiotoxicity and therapy-related malignancies. It is unclear whether these side effects are directly linked to their anticancer activity. Doxorubicin exerts two activities: DNA damage and chromatin damage. Here, we show that both activities conspire in the cardiotoxicity, while doxorubicin variants with only chromatin-damaging activity remain active anticancer drugs devoid of side effects. This challenges the concept that doxorubicin works primarily by inducing DNA double-strand breaks and reveals another major anticancer activity, chromatin damage. Translating these observations will yield anticancer drugs for patients that are currently excluded from doxorubicin treatment and improve the quality of life of cancer survivors.

The recognition of tissue damage via P2RX7 reduces the persistence of tissue-resident memory T cells (T _RM ).

Certain cytotoxic chemotherapeutic drugs are immunogenic, stimulating tumor immunity through mechanisms that are not completely understood. Here we show how the DNA-damaging drug cisplatin modulates tumor immunity. At the maximum tolerated dose (MTD), cisplatin cured 50% of mice with established murine TC-1 or C3 tumors, which are preclinical models of human papillomavirus (HPV)-associated cancer. Notably, the curative benefit of cisplatin relied entirely upon induction of tumor-specific CD8⁺ T cells. Mechanistic investigations showed that cisplatin stimulated tumor infiltration of inflammatory antigen-presenting cells (APC) expressing relatively higher levels of the T-cell costimulatory ligands CD70, CD80, and CD86. Cell death triggered by cisplatin was associated with the release of at least 19 proteins in the tumor environment that could act as damage-associated molecular patterns and upregulate costimulatory molecules, either alone or in concert, but the responsible proteins remain unknown. Essentially, the curative effect of cisplatin was abrogated in mice lacking expression of CD80 and CD86 on APCs. Furthermore, cisplatin treatment was improved by CTLA-4 blockade, which increases the availability of CD80/86 to bind to CD28. In contrast, there was no effect of CD27 stimulation, which replaces CD70 interaction. At the cisplatin MTD, cure rates could also be increased by vaccination with synthetic long peptides, whereas cures could also be achieved at similar rates at 80% of the MTD with reduced side effects. Our findings reveal an essential basis for the immunogenic properties of cisplatin, which are mediated by the induction of costimulatory signals for CD8⁺ T-cell–dependent tumor destruction. Cancer Res; 76(20); 6017–29. ©2016 AACR.

Upon cytomegalovirus (CMV) infection, large T-cell responses are elicited that remain high or even increase over time, a phenomenon named memory T-cell inflation. Besides, the maintained robust T-cell response, CMV-specific T cells seem to have a distinctive phenotype, characterized by an advanced differentiation state. Here, we will review this “special” differentiation status by discussing the cellular phenotype based on the expression of CD45 isoforms, costimulatory, inhibitory and natural killer receptors, adhesion and lymphocyte homing molecules, transcription factors, cytokines and cytotoxic molecules. In addition, we focus on whether the differentiation state of CMV-specific CD8 T cells is unique in comparison with other chronic viruses and we will discuss the possible impact of factors such as antigen exposure and aging on the advanced differentiation status of CMV-specific CD8 T cells.