Immunotherapy Goes Local: The Central Role of Lymph Nodes in Driving Tumor Infiltration and Efficacy

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.

Keywords: CTLA-4; PD-1; cancer; dendritic cell; immune check point; immune exclusion; t cell exhaustion; tumor draining lymph node.

Figure 1

A proposed model of tumor-induced immune suppression of draining lymph nodes and local therapeutic intervention opportunities to overcome T cell dysfunction and exclusion in early- and late-stage cancer development. (A) Schematic representation of how tumors, at early (left) and late stage (right), suppress the loco-regional immune response in the tumor as well as in the tumor-draining lymph nodes (TDLN). In early-stage disease, migratory DCs are hampered in their migration and activation [through release of suppressive factors in the tumor microenvironment (TME) and interactions with Tregs], resulting in suboptimal T cell priming and activation in the TDLN (generating dysfunctional T cells), conversion of Th cells to Tregs (see arrow), and reduced recruitment of Teff cells to the tumor. In late-stage disease, upon metastatic spread to the TDLN, LNR-cDC are profoundly suppressed, leading to the priming and expansion of dysfunctional progenitor exhausted T cells and Tregs in TDLN and poor recruitment of Teff to the tumor. Active suppression in the TME (with accumulating myeloid regulatory cells like M2 macrophages and a lack of mature DCs) contributes to the differentiation of terminally exhausted T cells and Treg recruitment with possible immune exclusion. (B) Suboptimal priming in the TDLN due to suppression of cDC, accompanied by excess PD-L1 surface expression, results in restrained T cell priming and deviated CD8+ T cell differentiation, marked by a reversibly dysfunctional state in early cancer development. Chronic high-dose (neo)-antigen stimulation in later stages of cancer development and progression will lead to the development of progenitor-exhausted and, ultimately, terminally exhausted T cells, marked by progressively higher PD-1 expression levels and the co-expression of other immune checkpoints, like LAG3, TIM3, and TIGIT. Typical markers for the different stages of dysfunction/exhaustion are listed (–27). Whereas progenitor exhausted T cells can be rescued by immune checkpoint blockade, terminal exhaustion is an irreversible state due to epigenetic programming. Local immunotherapy, targeted at TDLN conditioning, can restore the anti-tumor T cell response by promoting DC activation (e.g., through local injection of TLR-L): in early cancer stages without tumor involvement of TDLN this may suffice to reverse T cell dysfunction and kick-start effective systemic antitumor immunity. In advanced cancer additional immune checkpoint blockade in the TDLN will enable reinvigoration of progenitor exhausted T cells, which can then home to the tumor and populate the TME, thus overcoming immune exclusion. This image was created using Biorender.com.