Cytotoxic chemotherapeutics form the cornerstone of systemic treatment of many cancers. Patients are dosed at maximum tolerated dose (MTD), which is carefully determined in phase I studies. In contrast, in murine studies, dosages are often based on customary practice or small pilot studies, which often are not well documented. Consequently, research groups need to replicate experiments, resulting in an excess use of animals and highly variable dosages across the literature. In addition, while patients often receive supportive treatments in order to allow dose escalation, mice do not. These issues could affect experimental results and hence clinical translation. To address this, we determined the single-dose MTD in BALB/c and C57BL/6 mice for a range of chemotherapeutics covering the canonical classes, with clinical score and weight as endpoints. We found that there was some variation in MTDs between strains and the tolerability of repeated cycles of chemotherapy at MTD was drug-dependent. We also demonstrate that dexamethasone reduces chemotherapy-induced weight loss in mice. These data form a resource for future studies using chemotherapy in mice, increasing comparability between studies, reducing the number of mice needed for dose optimisation experiments and potentially improving translation to the clinic.

Cross‐presentation defines the unique capacity of an APC to present exogenous Ag via MHC class I molecules to CD8⁺ T cells. DCs are specialized cross‐presenting cells and as such have a critical role in antitumor immunity. DCs are routinely found within the tumor microenvironment, but their capacity for endogenous or therapeutically enhanced cross‐presentation is not well characterized. In this study, we examined the tumor and lymph node DC cross‐presentation of a nominal marker tumor Ag, HA, expressed by the murine mesothelioma tumor AB1‐HA. We found that tumors were infiltrated by predominantly CD11b⁺ DCs with a semimature phenotype that could not cross‐present tumor Ag, and therefore, were unable to induce tumor‐specific T‐cell activation or proliferation. Although tumor‐infiltrating DCs were able to take up, process, and cross‐present exogenous cell‐bound and soluble Ags, this was significantly impaired relative to lymph node DCs. Importantly, however, systemic chemotherapy using gemcitabine reversed the defect in Ag cross‐presentation of tumor DCs. These data demonstrate that DC cross‐presentation within the tumor microenvironment is defective, but can be reversed by chemotherapy. These results have important implications for anticancer therapy, particularly regarding the use of immunotherapy in conjunction with cytotoxic chemotherapy.

Agonistic anti-CD40 antibody is a potent stimulator of anti-tumor immune responses due to its action on both immune and tumor cells. It has the ability to “precondition” dendritic cells, allowing them to prime effective cytotoxic T-cell responses. Thus, anti-CD40 antibody provides an ideal therapy for combination with traditional cancer treatments (i.e., chemotherapy, surgery) in order to elicit immune-mediated anti-tumor effects. This review summarizes the mechanisms of action of agonistic anti-CD40, the use of mouse models to investigate its effects and combinations with other therapies in vivo, and current clinical trials combining humanized anti-CD40 antibody with chemotherapy and/or other immunotherapies.

Significance: Strongly implicated in effective antitumor immune responses, tumor mutation–derived antigens, or neoantigens, are one of the main targets for cancer vaccines despite uncertainty of the efficacy of this approach. Using a high-throughput screening method, we identify an endogenously immunogenic neoantigen in a commonly used mouse lung tumor model. We also found that the endogenous CD8 T cells specific for this neoantigen expand greatly upon treatment with immune checkpoint inhibitors or vaccination despite the lack of associated tumor regression in this model. In addition to informing neoantigen vaccination strategies and providing an accessible system for testing alternative therapeutics, our results provide insights into the mechanisms for the lack of response observed for a majority of patients treated with checkpoint blockade immunotherapies.