Highlights d Inter-and intra-metastatic immune infiltrates are heterogeneous in colorectal cancer d T cell densities from metastases increase following anti-EGFR treatment d Immunoscore (IS) outperforms PDL1 staining in metastatic biopsy diagnostic accuracy d IS and TB score from the least-infiltrated metastasis are most survival associated

CD30 antigen is a trans-membrane glycoprotein belonging to the tumor necrosis factor receptor superfamily. 1Upon stimulation, CD30 exerts pleiotropic effects on cell growth and survival, which largely depend on the NF-κB pathway activation.2 In normal or inflamed tissues, CD30 expression is restricted to medium/large activated Band/or T-lymphocytes, 1,3 while among lymphoproliferative disorders (LPDs) it was initially reported in classical Hodgkin's lymphoma (cHL) and anaplastic large cell lymphoma (ALCL).4 The specific and highly dense CD30 expression on the lymphomatous cells makes it an attractive target for drug-conjugated antibody-directed therapies, as first reported by Falini et al. in refractory cHL, 5 and later confirmed in experimental models on ALCL.6 In recent years, the anti-CD30 compounds again attracted clinical interest for the availability of a monomethyl auristatin E-conjugated anti-CD30 antibody (Brentuximab Vedotin) which produced encouraging results in clinical trials on refractory/resistant cHL or ALCL patients. 7,8Regarding peripheral T-cell lymphomas (PTCL) CD30 expression was observed in a subset of primary cutaneous LPDs, 9 enteropathy associated T-cell lymphoma (EATL, type 1), 10 extranodal NK/T-cell lymphoma nasal type (ENTL), 11 mycosis fungoides (MF), 12 transformed MF (t-MF) 13 and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS).14 Given the extremely poor prognosis of PTCL and the current unavailability of effective therapies, we assessed CD30 expression in 192 PTCL at onset, in order to assess the feasibility of immune-therapy administration in such tumors. The formalin-fixed paraffinembedded samples were retrieved from the archives of the Hematopathology Section, University of Bologna, Italy, and included: 42 angioimmunoblastic T-cell lymphomas (AITL), 41 MF (of which 9 t-MF), 12 EATL (Figure 1). The results for AITL in Table 1 are based on PAX5/CD30 double staining and refer to the PAX5 negative/CD30 positive neoplastic cells. In comparison to the single anti-CD30 staining, that also included PAX5 positive/CD30 positive B blasts, only 5 cases were down-graded (n=3 cases from 4+ to 3+, n=2 cases from 2+ to 1+). Interestingly, a relatively high percentage of MF showed a moderate positivity for CD30 (score ≥2+ 12.50%, 4 of 32): in keeping with our data, similar results have been recently reported in the literature.12 In all cases, staining intensity ranged from moderate to strong within the same section; the variability was often related to cell size, with small/medium cells showing moderate intensity and large cells a stronger one. No further correlation was found between CD30 expression and other morphological parameters.From a clinical perspective, these data potentially include some PTCL in the spectrum of the LPDs suitable for anti-CD30 immunotherapy: this is of special interest given the inefficacy of the current therapies. In particular, EATL type I, ENTL, t-MF and a subset of PTCL-NOS appear ideal candidates, whereas double staining on full sections for CD...

Following initial success in melanoma and lung tumours, immune checkpoint inhibitors (ICIs) are now well recognized as a major immunotherapy treatment modality for multiple types of solid cancers. In colorectal cancer (CRC), the small subset that is mismatch-repair-deficient and microsatellite-instability-high (dMMR/MSI-H) derive benefit from immunotherapy; however, the vast majority of patients with proficient MMR (pMMR) or with microsatellite stable (MSS) CRC do not. Immunoscore and the consensus molecular subtype classifications are promising biomarkers in predicting therapeutic efficacy in selected CRC. In pMRR/MSS CRC, biomarkers are also needed to understand the molecular mechanisms governing immune reactivity and to predict their relationship to treatment. The continuous development of such biomarkers would offer new perspectives and more personalized treatments by targeting oncological options, including ICIs, which modify the tumour-immune microenvironment. In this review, we focus on CRC and discuss the current status of ICIs, the role of biomarkers to predict response to immunotherapy, and the approaches being explored to render pMMR/MSS CRC more immunogenic through the use of combined therapies.