CD33 Expression on Peripheral Blood Monocytes Predicts Efficacy of Anti-PD-1 Immunotherapy Against Non-Small Cell Lung Cancer

Abstract

Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related deaths globally. Immune checkpoint blockade (ICB) has transformed cancer medicine, with anti-programmed cell death protein 1 (anti-PD-1) therapy now well-utilized for treating NSCLC. Still, not all patients with NSCLC respond positively to anti-PD-1 therapy, and some patients acquire resistance to treatment. There remains an urgent need to find markers predictive of anti-PD-1 responsiveness. To this end, we performed mass cytometry on peripheral blood mononuclear cells from 26 patients with NSCLC during anti-PD-1 treatment. Patients who responded to anti-PD-1 ICB displayed significantly higher levels of antigen-presenting myeloid cells, including CD9+ nonclassical monocytes, and CD33hi classical monocytes. Using matched pre-post treatment samples, we found that the baseline pre-treatment frequencies of CD33hi monocytes predicted patient responsiveness to anti-PD-1 therapy. Moreover, some of these classical and nonclassical monocyte subsets were associated with reduced immunosuppression by T regulatory (CD4+FOXP3+CD25+) cells in the same patients. Our use of machine learning corroborated the association of specific monocyte markers with responsiveness to ICB. Our work provides a high-dimensional profile of monocytes in NSCLC and links CD33 expression on monocytes with anti-PD-1 effectiveness in patients with NSCLC.

Restrained memory CD8+T cell responses favors viral persistence and elevated IgG responses in patients with severe Long COVID

“…3a-b ). CD33-expressing classical monocytes have previously been associated with anti-tumor immune responses and favourable responses to checkpoint inhibition in lung cancer 39 , and its blockade triggers spontaneous production of TNFα, IL-1b and IL-8 suggesting a repressive function in monocytes 40 . Expansion of CD33-expressing monocytes over CD33-negative monocytes in patients with Long COVID and elevated antibody responses ( Fig.…”

Blood Immune Cell Biomarkers in Lung Cancer Patients Undergoing Treatment with a Combination of Chemotherapy and Immune Checkpoint Blockade

“…High absolute neutrophil counts as well as a high NLR can identify non-responders to immune checkpoint inhibition; a meta-analysis reported that a high NLR resulted in a worse PFS and OS in NSCLC, melanoma, and genitourinary cancer treated with ICI therapy [ 24 ]. First results have been reported also for monocytes; using CyTOF mass cytometry, Olingy et al described a link of CD33-high classical monocytes to the effectiveness of ICI therapy in NSCLC patients [ 25 ]. Using multi-color flow cytometry of blood from NSCLC patients undergoing ICI monotherapy, a high NLR, a high frequency of HLA-DR low monocytes, and low DC percentages were defined as adverse factors for clinical response and patients’ survival [ 10 ].…”

“…In female study participants, a higher rate of hyperprogression was observed by Kanjanapan and coworkers [ 61 ]. Olingy et al described a lower frequency of CD33high monocytes in the blood of female NSCLC patients and discussed a link to a reduced responsiveness to ICI therapy [ 25 ]. Comparing female and male patients in our cohort, female patients had a lower PD-L1 tumor expression, were more often never-smokers, and had more metastases.…”

Blood-based biomarkers in patients with non-small cell lung cancer treated with immune checkpoint blockade

“…Multiple studies ( n = 3) involving 172 NSCLC patients have found that high peripheral monocyte populations at baseline associate with improved response rates, and in some cases improved PFS and OS (Table 6 ). Specifically, Olingy and colleagues, in 26 stage III-IV NSCLC patients treated with anti-PD-1, evaluated the association between monocyte subsets (identified by mass cytometry) and clinical response [ 79 ]. Responders (R, with a decreased tumor size or SD > 6 months) had greater baseline frequencies of CD33 hi classical monocytes (CD33 hi cMo, p = 0.014) and CD9 + nonclassical monocytes (CD9 + nMo, p = 0.012) than non-responding (NR) patients (Fig.…”