Abstract
Immune checkpoint blockade (ICB) has changed the therapeutic landscape of oncology but its impact is limited by primary or secondary resistance. ICB resistance has been related to a lack of T cells infiltrating into the tumor. Strategies to overcome this hurdle have so far focused on the tumor microenvironment, but have mostly overlooked the role of tumor-draining lymph nodes (TDLN). Whereas for CTLA-4 blockade TDLN have long since been implicated due to its perceived mechanism-of-action involving T cell priming, only recently has evidence been emerging showing TDLN to be vital for the efficacy of PD-1 blockade as well. TDLN are targeted by developing tumors to create an immune suppressed pre-metastatic niche which can lead to priming of dysfunctional antitumor T cells. In this review, we will discuss the evidence that therapeutic targeting of TDLN may ensure sufficient antitumor T cell activation and subsequent tumor infiltration to facilitate effective ICB. Indeed, waves of tumor-specific, proliferating stem cell-like, or progenitor exhausted T cells, either newly primed or reinvigorated in TDLN, are vital for PD-1 blockade efficacy. Both tumor-derived migratory dendritic cell (DC) subsets and DC subsets residing in TDLN, and an interplay between them, have been implicated in the induction of these T cells, their imprinting for homing and subsequent tumor control. We propose that therapeutic approaches, involving local delivery of immune modulatory agents for optimal access to TDLN, aimed at overcoming hampered DC activation, will enable ICB by promoting T cell recruitment to the tumor, both in early and in advanced stages of cancer.
Highlights
Over the past decade, it has become clear that for immune checkpoint blockade (ICB) to work, tumors need to contain sufficient numbers of infiltrating T cells [1, 2]
New insights point to the need for therapeutic targeting of tumor-draining lymph nodes (TDLN), rather than of the tumor microenvironment (TME), to secure proper antitumor T-cell generation and at the same time brisk tumor infiltration [5,6,7,8]
A significant negative correlation between the frequency and activation state of migratory conventional DC (cDC) subsets in melanoma sentinel lymph node (SLN) and primary tumor size (Breslow thickness), suggested that the developing primary melanoma created a pre-metastatic niche in the TDLN by suppressing the migration of antigen-carrying cDC from the tumor to the TDLN
Summary
It has become clear that for immune checkpoint blockade (ICB) to work, tumors need to contain sufficient numbers of infiltrating T cells [1, 2]. A growing number of studies are exploring the use of systemically administered immune checkpoint inhibitors (ICI) as neo-adjuvant therapy for patients in earlier (i.e., resectable) cancer stages [10,11,12,13]. As in this setting both the primary tumor and TDLN are still in place (rather than surgically removed in the adjuvant setting) this approach will enable simultaneous immune modulation of the TME and of TDLN. In this review we will discuss mechanisms underlying tumor-associated immune suppression of TDLN and how we can use this knowledge to devise new local intervention strategies aimed at harnessing TDLN to secure efficacy of cancer immunotherapy, both in early and in advanced stages of cancer development
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