Tumours support the T cell response

Although several studies have shown that naive CD8⁺ T cells can become activated in the tumour-draining lymph nodes during tumour outgrowth, whether naive CD8⁺ T cells are activated in the tumour mass itself remains to be established. Now Thompson and colleagues show that naive tumour-specific CD8⁺ T cells can infiltrate the tumour where they are activated, acquire an effector phenotype and proliferate in response to a specific antigen.

Tumours were established in mice using B16-ovalbumin (OVA) melanoma cells (which present OVA₂₅₇ peptide in an MHC class I-dependent manner). Following transfer of naive OT-I T cell receptor-transgenic T cells (which recognize the OVA₂₅₇ epitope), activated OT-I T cells, which were characterized by expression of CD25 and CD69, were found in the tumours; the authors also showed this in two other tumour models and with T cells specific for an endogenous tumour antigen. To directly show that OT-I T cells were activated in the tumour and not in the draining lymph nodes, lymph node development was inhibited in mice in utero. Whereas only naive OT-I T cells were present in the bone marrow, liver and lungs of these mice, activated OT-I T cells were found within tumours, both in a perivascular arrangement and in the parenchyma, showing that naive T cells infiltrate tumours.

Following treatment with the inhibitor FTY720, which blocks the migration of T cells out of lymph nodes, a significant number of divided tumour-specific T cells were still present in the tumours of FTY720-treated animals. A decrease in the number of divided OT-I T cells in non-draining lymph nodes compared with untreated controls was observed. However, this decrease was significantly greater than the decrease in the tumour, suggesting that intratumoral OT-I T cells did not arise in the draining lymph node. This was confirmed in lymph node-depleted mice; the size of the OT-I T cell population in the tumours of these mice was the same as in FTY720-treated animals with lymph nodes, suggesting that tumours can, without draining lymph node support, mediate CD8⁺ T cell activation and proliferation.

Does intratumoral activation of naive CD8⁺ T cells correlate with the generation of functional effector CD8⁺ T cells? Following ex vivo culture with OVA₂₅₇ peptide-pulsed stimulators, a significant number of OT-I T cells purified from B16-OVA tumours of FTY720-treated mice secreted interferon-γ (IFNγ) and expressed granzyme B and CD107a, which are markers of cytotoxic activity. Furthermore, the cells retained their functionality in vivo despite potential exposure to suppressive factors in the tumour microenvironment.

Finally, the authors attempted to identify whether cross-presentation by antigen-presenting cells (APCs) or direct presentation by tumour cells mediates CD8⁺ T cell activation. By using B16-F1 tumour cells, which express tyrosinase but lack the MHC class I molecule required to present the tyrosinase epitope (Tyr₃₆₉), it was shown that Tyr₃₆₉-specific CD8⁺ T cells upregulated CD25 and CD69 and could proliferate, degranulate and secrete IFNγ, supporting a role for cross-presentation by APCs. In addition, using chimeric animals in which bone marrow-derived populations cannot present OVA₂₅₇, OT-I T cell activation, proliferation and acquisition of effector function was similar to that in wild-type animals, providing evidence for direct presentation by tumour cells. Thus, the data show that both APCs and tumour cells have a role in CD8⁺ T cell activation in tumours.

So, tumours support the infiltration, activation, effector differentiation and proliferation of naive CD8⁺ T cells and, consequently, intratumoral CD8⁺ T cell activation may be a target for cancer immunotherapy.