## 5 Biomarkers of Response and/or Resistance to Immune Checkpoint Inhibitors
### Markers of Response and/or Resistance in Tumor Tissue
#### 5.2.2 PD-L1 Expression  
In order to predict the response to anti-PD-1/anti-PD-L1 therapy, the evaluation of PD-L1 expression on tumor cells with immunohistochemistry (IHC) seems to be the ideal \begin{table}
\begin{tabular}{c c c c c} \hline \hline  & & **Inflamed Class** & \multicolumn{2}{c}{**Non-Inflamed Class** (-45%)} \\ \hline  & **Active** & **Exhausted** & **Immune-Like** & **Intermediate** & **Excluded** \\ \hline  & & & Immune infiltrate & \\ \cline{2-5}  & & ++++ & ++++ & ++++ & ++++ & ---- \\ \cline{2-5}  & & \(\uparrow\) TIL/TLS abundance & & \(\downarrow\) TIL/TLS abundance \\ \cline{2-5}  & & \(\uparrow\) CD8\({}^{\ast}\) T cells and & \(\uparrow\) M2 macrophages & \(\uparrow\) CD8\({}^{\ast}\) T cells and & \(\uparrow\) M2 macrophages and T\({}_{\text{reg}}\) cells \\ \cline{2-5}  & & \(\uparrow\) T cells/nucleated cells fraction, polyclonal T & Oligoclonal & \(\downarrow\) T cells/nucleated cells fraction and diverse TCR repertoire \\ \cline{2-5}  & & cell expansion and diverse TCR repertoire & expansion & \(\downarrow\) immune-checkpoint molecules/CD8 \\ \cline{2-5}  & & \(\uparrow\) immune-checkpoint molecules/CD8 & \(\uparrow\) LAG3 & \(\downarrow\) LAG3 & \(\downarrow\) CD8 \\ \cline{2-5}  & & \(\uparrow\) PD-L1 & \(\uparrow\) PD-L1 & \(\uparrow\) CTLA4 & \(\downarrow\) CTLA4 & \(\downarrow\) PD-L1 \\ \cline{2-5}  & & \(\uparrow\) IFN\(\gamma\), GZMB, PRFI, PD-1 signaling & \(\downarrow\) IFN\(\gamma\), GZMB, PRFI, PD-1 signaling \\ \cline{2-5}  & & Liquid Biopsy-based cytokine prediction of the inflamed class & \(\downarrow\) CXCL1, CXCL11, CCL15 \\ \hline  & & \(\uparrow\) TGF\(\beta\) & \(\uparrow\) Wnt-\(\beta\)catenin & \(\uparrow\) Wnt-\(\beta\)catenin & \(\uparrow\) PTK2 \\ \cline{2-5}  & & \(\uparrow\) Hoshida S1 & \(\uparrow\) Hoshida S2 & \(\uparrow\) Hoshida S2/3 \\ \cline{2-5}  & & \(\uparrow\) Chiang IFN & \(\uparrow\) Chiang CTNNB1 & \(\uparrow\) Chiang Poly7 & \(\uparrow\) Chiang CTNNB1 \\ \cline{2-5}  & & & Chromosomal aberrations & \\ \cline{2-5}  & & \(\uparrow\) \(\leftarrow\) \(\leftarrow\) \(\leftarrow\) & ++++ & ++++ \\ \cline{2-5}  & & & \(\uparrow\) deletions at 16p13.13, & Amplification 8q24.3 \\ \cline{2-5}  & & & \(\uparrow\) CTNNB1 & \(\uparrow\) TP53 mutation & \(\uparrow\) CTNNB1 mutation \\ \hline  & & 192 immune-related genes & Hypomethylation of & \\ differentially methylated & HLA-I related genes & Hypomethylation of & \\ \cline{2-5}  & & Abbreviations: TIL; tumor-infiltrating lymphocytes; TLS, tertiary lymphoid structures; TCR, T cell receptor; PD-L1, programmed death-ligand 1; LAG3, lymphocyte-activation gene 3; CTLA4, cytotoxic T lymphocyte antigen 4; INF\(\gamma\); interferon \(\gamma\); GZMB, Granzyme B; PRFI, perform 1; PD-1, programmed death protein 1; CXCL9, chemokine ligand 9; CXCL10, chemokine ligand 10; CXCL11, chemokine ligand 11; CCL5, chemokine ligand 5; TCF\(\beta\), transforming growth factor \(\beta\); CTNNB1,catenin beta 1; T\({}_{\text{reg}}\), T regulatory cells. \(\uparrow\) = increase; \(\downarrow\) = decrease. \\ \hline \hline \end{tabular}
\end{table} 
Table 3: Schematic representation of histopathological and molecular features associated with immune classes in HCC ([PERSON] et al., 2023 [34]). biomarker. Currently, PD-L1 IHC is used to decide whether to treat patients with NSCLC with anti-PD-1 therapy [99,100]. In particular, pembrolizumab is approved for NSCLC patients who are PD-L1\({}^{+}\) (defined as PD-L1 on \(\geq\)50% of tumor cells in the first-line and \(\geq\)1% in the second-line). Nevertheless, despite multiple studies having demonstrated a positive correlation between PD-L1 expression and outcome in different tumor types [101, 102, 103, 104], PD-L1 expression remains an imperfect predictor of ICIs response. In particular, evidence of a predictive role for PD-L1 immunostaining in HCC is elusive [3]. [PERSON] et al.