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.

Phages and cancer immunity: Gut bacteria are involved in the education of T cell immune responses, and the intestinal ecosystem influences anticancer immunity. Fluckiger et al. report microbial antigens that might cross-react with antigens associated with tumor cells. They found that a type of intestinal bacteria called enterococci harbor a bacteriophage that modulates immune responses. In mouse models, administration of enterococci containing the bacteriophage boosted T cell responses after treatment with chemotherapy or programmed cell death protein 1 (PD-1) blockade. In humans, the presence of the bacteriophage was associated with improved survival after PD-1 immunotherapy. A fraction of human T cells specific for naturally processed melanoma epitopes appeared to be able to recognize microbial peptides. This “molecular mimicry” may represent cross-reactivity between tumors and microbial antigens. Science , this issue p. 936

Recent studies have suggested a close relationship between CD4⁺FOXP3⁺regulatory T cells (Tregs) and proinflammatory IL-17-producing T helper cells (T_H17) expressing the lineage-specific transcription factor RORγt. We report here the unexpected finding that human memory Tregs secrete IL-17 ex vivo and constitutively express RORγt. IL-17-secreting Tregs share some phenotypic and functional features with conventional T_H17 cells, expressing high levels of CCR4 and CCR6 and low levels of CXCR3. However, unlike conventional T_H17 cells, they express low levels of CD161 and mostly fail to cosecrete IL-22 and TNF-α ex vivo. Ex vivo secretion of IL-17 and constitutive expression of RORγt by human memory Tregs suggest that, in addition to their well-known suppressive functions, these cells likely play additional, as yet undescribed, proinflammatory functions.

CD4⁺CD25⁺ Tregs play a central role in the maintenance of peripheral self tolerance by keeping autoreactive T cells in check. Whereas the thymic origin of CD4⁺CD25⁺ Tregs, as a distinct lineage, has been inferred, understanding of their developmental pathways has remained elusive. In both mice and humans, peripheral CD4⁺CD25⁺ Treg populations have been described as composed of antigen-experienced T cells that fail to significantly proliferate following TCR stimulation but suppress proliferation and effector functions of CD25^– T cells. Here we show that analysis of CD25 expression in human circulating CD4⁺ T lymphocytes with respect to their in vivo differentiation stages identifies a distinct subset of CD25⁺CCR7⁺CD62L⁺CTLA-4⁺FOXP3⁺ cells contained in the CD45RA⁺/RO^– naive fraction. The subset, which we have named natural naive Tregs (NnTregs), is prominent in young adults and decreases with age together with the total naive CD4⁺ population. NnTregs are anergic following stimulation in the absence of IL-2 and exert ex vivo cell-cell contact–mediated suppressor functions. In addition, they proliferate in response to stimulation with autologous APCs, which indicates a high enrichment in T cells bearing self-reactive TCRs. The definition of this subset has important implications for the analysis of human naturally occurring Tregs and for their targeting in therapeutic immune interventions.

The use of recombinant tumor antigen proteins is a realistic approach for the development of generic cancer vaccines, but the potential of this type of vaccines to induce specific CD8 ⁺ T cell responses, through in vivo cross-priming, has remained unclear. In this article, we report that repeated vaccination of cancer patients with recombinant NY-ESO-1 protein, Montanide ISA-51, and CpG ODN 7909, a potent stimulator of B cells and T helper type 1 (Th1)-type immunity, resulted in the early induction of specific integrated CD4 ⁺ Th cells and antibody responses in most vaccinated patients, followed by the development of later CD8 ⁺ T cell responses in a fraction of them. The correlation between antibody and T cell responses, together with the ability of vaccine-induced antibodies to promote in vitro cross-presentation of NY-ESO-1 by dendritic cells to vaccine-induced CD8 ⁺ T cells, indicated that elicitation of NY-ESO-1-specific CD8 ⁺ T cell responses by cross-priming in vivo was associated with the induction of adequate levels of specific antibodies. Together, our data provide clear evidence of in vivo cross-priming of specific cytotoxic T lymphocytes by a recombinant tumor antigen vaccine, underline the importance of specific antibody induction for the cross-priming to occur, and support the use of this type of formulation for the further development of efficient cancer vaccines.