Fig. 3: CINI immunosuppression and immune exhaustion extends beyond the perineural niches into the general tumour microenvironment.
From: Cancer-induced nerve injury promotes resistance to anti-PD-1 therapy
a, Quantification of nerves invaded by SCC (MOC2 cells) injected into mouse whisker pads (n = 12). Nerve invasion index: number of invaded nerves/total number nerves. Data are mean ± s.e.m. mIF shows an invaded nerve (asterisk) lacking MBP, suggesting myelin degradation. CK, cytokeratin. b, mIF analysis of the whisker pad tumours collected over time. c, mIF tumours collected from treatment-naive patients with cSCC and PDAC; nerves are indicated by the dashed lines. d, Immune cell density in the perineural niche in treatment-naive PDAC samples (n = 7), based on CosMx analysis. TANs were classified as healthy (n = 11), intermediate (n = 36) and injured (n = 44). The box plots show the median (centre line), 25th and 75th percentiles (box limits) and minimum and maximum values (whiskers). Statistical analysis was performed using two-tailed Mann–Whitney exact tests. e, Heat map of nerve-injury-related proteins in the perineural niches among the patients in our anti-PD-1 cSCC trial, measured using DSP, with data transformed into z scores (Supplementary Table 8). f, Bubble heat map based on a DSP protein matrix showing the Pearson’s correlation coefficients between immune and neural proteins expressed in the perineural niches of neoadjuvant-treated tumours (patients in the anti-PD-1 cSCC trial). Statistical analysis was performed using pairwise Pearson correlation. g, mIF-based cell density according to clinical response to anti-PD-1 therapy. n = 6 responders, n = 7 non-responders. Statistical analysis was performed using two-tailed Student’s t-tests with the assumption of equal variances (pooled t-test). h, Spatial transcriptomics of tumour samples from an independent treatment-naive cohort of patients with cSCC (see the main text), assessing the co-localization of three phenotypes: CINI, immunosuppressive inflammation and antitumoural immunity (55-μm resolution per spot). i, Correlation of the immune cell density between TAN perineural niches and nerve-remote area in the TME of the SCC cohort in Fig. 2h, according to the presence of PNI. n = 32 patients, and n = 25 (PNI− nerves) and n = 25 (PNI+ nerves) ROIs. A linear regression line (blue) was created based on the least-squares method; the shaded region shows the 95% CI; statistical analysis was performed using pairwise Pearson’s correlation. Scale bars, 50 μm (a), 100 μm (c, rows 2 and 4), 200 μm (c, rows 1 and 3).
