CD68 and PD-L1: Better Together?

Cluster of differentiation 68 (CD68) is a glycoprotein expressed primarily by macrophages that facilitates target identification by binding to tissue- or organ-specific lectins or selectins. CD68 is a macrophage panmarker, enabling identification of the entire macrophage population regardless of phenotype. M1 macrophages are proinflammatory and antitumoral, while the M2 phenotype is associated with protumoral and immunosuppressive effects¹.

Further investigation of not only the colocalization of CD68 and PD-L1, but also any potential association between the colocalization of these two markers and clinical outcome is warranted to explore the potential for combination of anti-PD-1/PD-L1 drugs with drugs that target TAMs. Additional studies are also needed to further elucidate the role of CD68+ PD-L1+ cells specifically within the tumor microenvironment, as well as the impact of various anticancer treatments on these cells.

In this vein, multiple investigators have examined the use of an "immunuoscore" based on CD68 and PD-L1 to either predict the response to anticancer therapy or to select patients for therapy based on the likelihood of their response to treatment.^7-8 To date, work on the association between CD68 and PD-L1 expression has been completed in breast cancer, non-small cell lung cancer, ovarian cancer, Hodgkin lymphoma, and bladder cancer.^9-11 Continued work in this area should provide additional information regarding the significance of CD68 and PD-L1 colocalization, as well as potential associated implications for cancer treatment.

Tumor cells actively recruit M2 macrophages through paracrine loops or direct contact with membrane molecules. Programmed cell death protein 1 (PD-1) and its ligand (PD-L1) represent one pair of such membrane molecules, and they play an important role in recruitment of tumor-associated macrophages (TAMs).¹

CD68 and PD-L1 are each integral to tumorigenesis and the response (or lack of response) to anticancer therapy. For example, increased CD68+ macrophage index is associated with metastasis, shorter disease-free interval, poor prognosis, and reduced overall survival in multiple types of cancer.^1-4 Similarly, PD-L1+ TAMs have been identified at the interface between malignant and healthy tissue, and may create an immunoprotective barrier around the tumor, thereby increasing resistance to immunotherapy. In contrast, inhibition of PD-L1 downregulates M2 macrophages and subsequently decreases their protumoral effects.¹

Given the distinct individual roles CD68 and PD-L1 play in tumor progression and response to immunotherapy, the exact distribution and co-localization of these two molecules may further affect these outcomes. Indeed, in patients with diffuse large B-cell lymphoma, up to 18.9% of tumor cells were CD68+, and 30-52% of these CD68+ cells were PL-L1+.⁵ This is in comparison to a median of 55% and 30% of CD68+ cells identified as PD-L1+ in patients with squamous cell carcinoma and adenocarcinoma, respectively.⁶ Thus, across cancer types, colocalization of CD68 and PD-L1 appears to be approximately 30-55%.