Immune Cell Infiltration and Tertiary Lymphoid Structures as Determinants of Antitumor Immunity

Abstract

Limited representation of intratumoral immune cells is a major barrier to tumor control. However, simply enhancing immune responses in tumor-draining lymph nodes or through adoptive transfer may not overcome the limited ability of tumor vasculature to support effector infiltration. An alternative is to promote a sustained immune response intratumorally. This idea has gained traction with the observation that many tumors are associated with tertiary lymphoid structures (TLS), which organizationally resemble lymph nodes. These peri- and intratumoral structures are usually, but not always, associated with positive prognoses in patients. Preclinical and clinical data support a role for TLS in modulating immunity in the tumor microenvironment. However, there appear to be varied functions of TLS, potentially based on their structure or location in relation to the tumor or the origin or location of the tumor itself. Understanding more about TLS development, composition, and function may offer new therapeutic opportunities to modulate antitumor immunity.

Figure 1

Intratumoral TLS with a nonclassical organization are found in association with PNAd⁺ vasculature in intraperitoneal but not subcutaneous murine B16-OVA melanoma.

Figure 2

Multispectral imaging of TLS in human melanoma metastases localized outside the tumor area (A); peritumoral, at the peripheral edge of tumor (B–D); or intratumorally (E–F). All scale bars are equal to 100 μm. Artefactual tissue creases due to sectioning can be seen on images B and C.

Figure 3

Model for the formation of nonclassical and classical tumor associated TLS.