The emerging interplay between recirculating and tissue-resident memory T cells in cancer immunity: lessons learned from PD-1/PD-L1 blockade therapy and remaining gaps

Remarkable progress has been made in the field of anti-tumor immunity, nevertheless many questions are still open. Thus, even though memory T cells have been implicated in long-term anti-tumor protection, particularly in prevention of cancer recurrence, the bases of their variable effectiveness in tumor patients are poorly understood. Two types of memory T cells have been described according to their traffic pathways: recirculating and tissue-resident memory T cells. Recirculating tumor-specific memory T cells are found in the cell infiltrate of solid tumors, in the lymph and in the peripheral blood, and they constantly migrate in and out of lymph nodes, spleen, and bone marrow. Tissue-resident tumor-specific memory T cells (TRM) permanently reside in the tumor, providing local protection. Anti-PD-1/PD-L1, a type of immune checkpoint blockade (ICB) therapy, can considerably re-invigorate T cell response and lead to successful tumor control, even in patients at advanced stages. Indeed, ICB has led to unprecedented successes against many types of cancers, starting a ground-breaking revolution in tumor therapy. Unfortunately, not all patients are responsive to such treatment, thus further improvements are urgently needed. The mechanisms underlying resistance to ICB are still largely unknown. A better knowledge of the dynamics of the immune response driven by the two types of memory T cells before and after anti-PD-1/PD-L1 would provide important insights on the variability of the outcomes. This would be instrumental to design new treatments to overcome resistance. Here we provide an overview of T cell contribution to immunity against solid tumors, focusing on memory T cells. We summarize recent evidence on the involvement of recirculating memory T cells and TRM in anti-PD-1/PD-L1-elicited antitumor immunity, outline the open questions in the field, and propose that a synergic action of the two types of memory T cells is required to achieve a full response. We argue that a T-centric vision focused on the specific roles and the possible interplay between TRM and recirculating memory T cells will lead to a better understanding of anti-PD-1/PD-L1 mechanism of action, and provide new tools for improving ICB therapeutic strategy.