Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors.

We investigated the role of chemokines in regulating T cell accumulation in solid tumors. CCL5 and CXCL9 overexpression was associated with CD8+ T cell infiltration in solid tumors. T cell infiltration required tumor cell-derived CCL5 and was amplified by IFN-γ-inducible, myeloid cell-secreted CXCL9. CCL5 and CXCL9 coexpression revealed immunoreactive tumors with prolonged survival and response to checkpoint blockade. Loss of CCL5 expression in human tumors was associated with epigenetic silencing through DNA methylation. Reduction of CCL5 expression caused tumor-infiltrating lymphocyte (TIL) desertification, whereas forced CCL5 expression prevented Cxcl9 expression and TILs loss, and attenuated tumor growth in mice through IFN-γ. The cooperation between tumor-derived CCL5 and IFN-γ-inducible CXCR3 ligands secreted by myeloid cells is key for orchestrating T cell infiltration in immunoreactive and immunoresponsive tumors.

Dendritic cells and CD28 costimulation are required to sustain virus-specific CD8+ T cell responses during the effector phase in vivo.

Although much is known about the initiation of immune responses, much less is known about what controls the effector phase. CD8(+) T cell responses are believed to be programmed in lymph nodes during priming without any further contribution by dendritic cells (DCs) and Ag. In this study, we report the requirement for DCs, Ag, and CD28 costimulation during the effector phase of the CD8(+) T cell response. Depleting DCs or blocking CD28 after day 6 of primary influenza A virus infection decreases the virus-specific CD8(+) T cell response by inducing apoptosis, and this results in decreased viral clearance. Furthermore, effector CD8(+) T cells adoptively transferred during the effector phase fail to expand without DC, CD28 costimulation, and cognate Ag. The absence of costimulation also leads to reduced survival of virus-specific effector cells as they undergo apoptosis mediated by the proapoptotic molecule Bim. Finally, IL-2 treatment restored the effector response in the absence of CD28 costimulation. Thus, in contrast to naive CD8(+) T cells, which undergo an initial Ag-independent proliferation, effector CD8(+) T cells expanding in the lungs during the effector phase require Ag, CD28 costimulation, and DCs for survival and expansion. These requirements would greatly impair effector responses against viruses and tumors that are known to inhibit DC maturation and in chronic infections and aging where CD28(-/-) CD8(+) T cells accumulate.

Costimulation signals for memory CD8+ T cells during viral infections.

Costimulation signals have been recognized as critical for optimal T-cell responses and result from important interactions between receptors on the surface of T cells and their ligands on antigen-presenting cells. Two families of receptors, the CD28 family and the tumor necrosis factor receptor (TNFR) family, have been found to be major players in providing costimulation to CD8+ T cells. Recent studies using viral infection models have highlighted the importance of CD28 costimulation signals during memory responses against viruses. Programmed death-1 (PD-1), another member of the CD28 family, may contribute to functional defects of helpless memory CD8+ T cells. Members of the TNFR family, such as CD27, 4-1BB, CD40, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), and OX40, have also been implicated in the survival, generation, maintenance, and quality of virus-specific memory CD8+T cells. The delivery of costimulatory molecules such as CD28, 4-1BB, and OX40 can help boost the generation and function of virus-specific memory CD8+ T cells. The use of costimulatory molecules as adjuvants, along with viral antigens in vaccines, may facilitate the generation of effective antigen-specific memory CD8+ T-cell responses. Understanding the costimulatory requirements of memory CD8+ T cells, therefore, may lead to improved vaccines that target anti-viral CD8+ T-cell memory.